BioPAX pathway converted from "Gene expression (Transcription)" in the Reactome database. Gene expression (Transcription) Gene expression encompasses transcription and translation and the regulation of these processes. RNA Polymerase I Transcription produces the large preribosomal RNA transcript (45S pre-rRNA) that is processed to yield 18S rRNA, 28S rRNA, and 5.8S rRNA, accounting for about half the RNA in a cell. RNA Polymerase II transcription produces messenger RNAs (mRNA) as well as a subset of non-coding RNAs including many small nucleolar RNAs (snRNA) and microRNAs (miRNA). RNA Polymerase III Transcription produces transfer RNAs (tRNA), 5S RNA, 7SL RNA, and U6 snRNA. Transcription from mitochondrial promoters is performed by the mitochondrial RNA polymerase, POLRMT, to yield long transcripts from each DNA strand that are processed to yield 12S rRNA, 16S rRNA, tRNAs, and a few RNAs encoding components of the electron transport chain. Regulation of gene expression can be divided into epigenetic regulation, transcriptional regulation, and post-transcription regulation (comprising translational efficiency and RNA stability). Epigenetic regulation of gene expression is the result of heritable chemical modifications to DNA and DNA-binding proteins such as histones. Epigenetic changes result in altered chromatin complexes that influence transcription. Gene Silencing by RNA mostly occurs post-transcriptionally but can also affect transcription. Small RNAs originating from the genome (miRNAs) or from exogenous RNA (siRNAs) are processed and transferred to the RNA-induced silencing complex (RISC), which interacts with complementary RNA to cause cleavage, translational inhibition, or transcriptional inhibition. Authored: Kornblihtt, AR, Proudfoot, NJ, Caudy, M, D'Eustachio, P, 2008-12-03 01:43:15 Authored: Comai, L, Conaway, Joan W, Conaway, Ron C, Gustafsson, CM, Hernandez, Nouria, Hu, P, Larsson, Nils-Göran, Proudfoot, Nicholas J, Reinberg, Danny, Timmers, Marc, 2003-09-11 Reviewed: Paule, M, Zhao, X, Willis, I, 0000-00-00 00:00:00 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 RNA Polymerase I Transcription RNA polymerase (Pol) I (one of three eukaryotic nuclear RNA polymerases) is devoted to the transcription of the ribosomal DNA genes, which are found in multiple arrayed copies in every eukaryotic cell. These genes encode for the large ribosomal RNA precursor, which is then processed into the three largest subunits of the ribosomal RNA, the 18S, 28S, and 5.8S RNAs. In human cells the rDNA gene clusters are localized on the short arm of the five pairs of the acrocentric chromosomes. The rRNA promoter has two essential and specially spaced sequences: a CORE element and an upstream control element (UCE, also called UPE). The CORE element of the human promoter overlaps with the transcription start site, extending from 20 to 45, and is required for specific initiation of transcription. <br> The polymerase is a multisubunit complex, composed of two large subunits (the most conserved portions include the catalytic site that shares similarity with other eukaryotic and bacterial multisubunit RNA polymerases) and a number of smaller subunits. Under a number of experimental conditions the core is competent to mediate ribonucleic acid synthesis, in vivo however, it requires additional factors to select the appropriate template. In humans the RNA transcript (45S) is approximately 13,000 nucleotides long. Before leaving the nucleus as assembled ribosomal particles, the 45S rRNA is cleaved to give one copy each of the 28S rRNA, the 18S rRNA, and the 5.8S rRNA. Equal quantities of the three rRNAs are produced by initially transcribing them as one transcript. Authored: Comai, L, 2003-07-03 17:13:29 Reviewed: Paule, M, Zhao, X, 0000-00-00 00:00:00 Edited: Gillespie, ME, 0000-00-00 00:00:00 RNA Polymerase I Promoter Clearance Promoter clearance is one of the rate-limiting steps in Polymerase I transcription. This step is composed of three phases, promoter opening, transcription initiation and promoter escape. Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 RNA Polymerase I Promoter Opening The activity of the upstream binding factor (UBF-1) plays an important role in the regulation of rRNA synthesis. Studies reveal that phosphorylation of UBF-1 is required for its interaction with the RNA polymerase I complex, suggesting that phosphorylation of UBF-1 bound to the rDNA promoter during promoter opening modulates the assembly of the transcription initiation complex. Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 LEFT-TO-RIGHT UBF-1 Binds rDNA Promoter UBF-1 binds directly to the CORE and UCE elements of the ribosomal DNA promoter. This binding is mediated by the HMG boxes (primarily HMG box1). Phosphorylation may play a role in the modulation of UBF's DNA binding activity, as well as in subsequent steps. UBF is thought to bind DNA in a conformation specific manner (as opposed to a sequence specific manner). The binding of UBF to the minor groove of DNA induces strong DNA bending. Methylcytosine in the promoter of a rRNA gene binds MBD2 (and possibly other Methyl Domain Binding Proteins) and prevents the transcription factor UBF-1 from binding. In mouse, methylation of the cytosine 133 nucleotides upstream of the start of transcription is sufficient. In the human rRNA promoter methylation of cytosines 9, 102, and 347 nucleotides upstream inhibit transcription. Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 rDNA Promoter Reactome DB_ID: 73682 nucleoplasm GENE ONTOLOGY GO:0005654 Reactome Database ID Release 78 73682 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73682 Reactome R-ALL-73682 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-73682.2 Reactome http://www.reactome.org ChEBI 61120 additional information MI MI:0361 UBF UBTF Nucleolar transcription factor 1 (Upstream binding factor 1) (UBF-1) (Autoantigen NOR-90) Nucleolar transcription factor 1 Upstream binding factor 1 UBF-1 Autoantigen NOR-90 Reactome DB_ID: 73683 UniProt:P17480 UBTF UBTF UBF UBF1 FUNCTION Recognizes the ribosomal RNA gene promoter and activates transcription mediated by RNA polymerase I through cooperative interactions with the transcription factor SL1/TIF-IB complex. It binds specifically to the upstream control element.SUBUNIT Homodimer (By similarity). Interacts with TBP (PubMed:7982918). Interacts with TAF1A (PubMed:7491500). Interacts with RASL11A (By similarity). Binds to IRS1 and PIK3CA (By similarity). Interacts with DHX33 (PubMed:21930779). Interacts with PHF6 (PubMed:23229552). Interacts with CEBPA (isoform 1 and isoform 4) (PubMed:20075868). Interacts with DDX11 (PubMed:26089203). Interacts with NOP53 (PubMed:27729611).PTM Phosphorylated and activated by PIK3CA. Homo sapiens NCBI Taxonomy 9606 UniProt P17480 1 EQUAL 764 EQUAL Reactome Database ID Release 78 73683 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73683 Reactome R-HSA-73683 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73683.1 UBF-1:rDNA Promoter Reactome DB_ID: 73684 1 1 Reactome Database ID Release 78 73684 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73684 Reactome R-HSA-73684 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73684.1 Reactome Database ID Release 78 73718 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73718 Reactome R-HSA-73718 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73718.5 2330041 Pubmed 1990 Nucleolar transcription factor hUBF contains a DNA-binding motif with homology to HMG proteins. Jantzen, HM Bell, SP Tjian, R Nature 344:830-6 INHIBITION Reactome Database ID Release 78 427347 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=427347 Reactome R-HSA-427347 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-427347.1 Nucleosome Nucleosome (Deacetylated) Reactome DB_ID: 427402 Converted from EntitySet in Reactome Histone H3 Reactome DB_ID: 212293 HIST1H3A Histone H3.1 Histone H3a Histone H3b Histone H3c Histone H3d Histone H3f Histone H3h Histone H3i Histone H3j Histone H3k Histone H3l Reactome DB_ID: 212070 UniProt:P68431 H3C1 H3C1 H3FA HIST1H3A H3C2 H3FL HIST1H3B H3C3 H3FCHIST1H3C H3C4 H3FB HIST1H3D H3C6 H3FD HIST1H3E H3C7 H3FI HIST1H3F H3C8 H3FH HIST1H3G H3C10 H3FK HIST1H3H H3C11 H3FF HIST1H3I H3C12 H3FJ HIST1H3J FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.DEVELOPMENTAL STAGE Expressed during S phase, then expression strongly decreases as cell division slows down during the process of differentiation.PTM Acetylation is generally linked to gene activation. Acetylation on Lys-10 (H3K9ac) impairs methylation at Arg-9 (H3R8me2s). Acetylation on Lys-19 (H3K18ac) and Lys-24 (H3K24ac) favors methylation at Arg-18 (H3R17me). Acetylation at Lys-123 (H3K122ac) by EP300/p300 plays a central role in chromatin structure: localizes at the surface of the histone octamer and stimulates transcription, possibly by promoting nucleosome instability.PTM Citrullination at Arg-9 (H3R8ci) and/or Arg-18 (H3R17ci) by PADI4 impairs methylation and represses transcription.PTM Asymmetric dimethylation at Arg-18 (H3R17me2a) by CARM1 is linked to gene activation. Symmetric dimethylation at Arg-9 (H3R8me2s) by PRMT5 is linked to gene repression. Asymmetric dimethylation at Arg-3 (H3R2me2a) by PRMT6 is linked to gene repression and is mutually exclusive with H3 Lys-5 methylation (H3K4me2 and H3K4me3). H3R2me2a is present at the 3' of genes regardless of their transcription state and is enriched on inactive promoters, while it is absent on active promoters.PTM Methylation at Lys-5 (H3K4me), Lys-37 (H3K36me) and Lys-80 (H3K79me) are linked to gene activation. Methylation at Lys-5 (H3K4me) facilitates subsequent acetylation of H3 and H4. Methylation at Lys-80 (H3K79me) is associated with DNA double-strand break (DSB) responses and is a specific target for TP53BP1. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are linked to gene repression. Methylation at Lys-10 (H3K9me) is a specific target for HP1 proteins (CBX1, CBX3 and CBX5) and prevents subsequent phosphorylation at Ser-11 (H3S10ph) and acetylation of H3 and H4. Methylation at Lys-5 (H3K4me) and Lys-80 (H3K79me) require preliminary monoubiquitination of H2B at 'Lys-120'. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are enriched in inactive X chromosome chromatin. Monomethylation at Lys-57 (H3K56me1) by EHMT2/G9A in G1 phase promotes interaction with PCNA and is required for DNA replication.PTM Phosphorylated at Thr-4 (H3T3ph) by HASPIN during prophase and dephosphorylated during anaphase. Phosphorylation at Ser-11 (H3S10ph) by AURKB is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. In addition phosphorylation at Ser-11 (H3S10ph) by RPS6KA4 and RPS6KA5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or UV irradiation and result in the activation of genes, such as c-fos and c-jun. Phosphorylation at Ser-11 (H3S10ph), which is linked to gene activation, prevents methylation at Lys-10 (H3K9me) but facilitates acetylation of H3 and H4. Phosphorylation at Ser-11 (H3S10ph) by AURKB mediates the dissociation of HP1 proteins (CBX1, CBX3 and CBX5) from heterochromatin. Phosphorylation at Ser-11 (H3S10ph) is also an essential regulatory mechanism for neoplastic cell transformation. Phosphorylated at Ser-29 (H3S28ph) by MAP3K20 isoform 1, RPS6KA5 or AURKB during mitosis or upon ultraviolet B irradiation. Phosphorylation at Thr-7 (H3T6ph) by PRKCB is a specific tag for epigenetic transcriptional activation that prevents demethylation of Lys-5 (H3K4me) by LSD1/KDM1A. At centromeres, specifically phosphorylated at Thr-12 (H3T11ph) from prophase to early anaphase, by DAPK3 and PKN1. Phosphorylation at Thr-12 (H3T11ph) by PKN1 is a specific tag for epigenetic transcriptional activation that promotes demethylation of Lys-10 (H3K9me) by KDM4C/JMJD2C. Phosphorylation at Thr-12 (H3T11ph) by chromatin-associated CHEK1 regulates the transcription of cell cycle regulatory genes by modulating acetylation of Lys-10 (H3K9ac). Phosphorylation at Tyr-42 (H3Y41ph) by JAK2 promotes exclusion of CBX5 (HP1 alpha) from chromatin.PTM Monoubiquitinated by RAG1 in lymphoid cells, monoubiquitination is required for V(D)J recombination (By similarity). Ubiquitinated by the CUL4-DDB-RBX1 complex in response to ultraviolet irradiation. This may weaken the interaction between histones and DNA and facilitate DNA accessibility to repair proteins.PTM Lysine deamination at Lys-5 (H3K4all) to form allysine is mediated by LOXL2. Allysine formation by LOXL2 only takes place on H3K4me3 and results in gene repression.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Butyrylation of histones marks active promoters and competes with histone acetylation. It is present during late spermatogenesis.PTM Succinylation at Lys-80 (H3K79succ) by KAT2A takes place with a maximum frequency around the transcription start sites of genes (PubMed:29211711). It gives a specific tag for epigenetic transcription activation (PubMed:29211711). Desuccinylation at Lys-123 (H3K122succ) by SIRT7 in response to DNA damage promotes chromatin condensation and double-strand breaks (DSBs) repair (PubMed:27436229).PTM Serine ADP-ribosylation constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:30257210). Serine ADP-ribosylation at Ser-11 (H3S10ADPr) is mutually exclusive with phosphorylation at Ser-11 (H3S10ph) and impairs acetylation at Lys-10 (H3K9ac) (PubMed:30257210).PTM Serotonylated by TGM2 at Gln-6 (H3Q5ser) during serotonergic neuron differentiation (PubMed:30867594). H3Q5ser is associated with trimethylation of Lys-5 (H3K4me3) and enhances general transcription factor IID (TFIID) complex-binding to H3K4me3, thereby facilitating transcription (PubMed:30867594).PTM Dopaminylated by TGM2 at Gln-6 (H3Q5dop) in ventral tegmental area (VTA) neurons (PubMed:32273471). H3Q5dop mediates neurotransmission-independent role of nuclear dopamine by regulating relapse-related transcriptional plasticity in the reward system (By similarity).PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.DISEASE HIST1H3B or HIST1H3C mutations affecting residue Lys-37 of histone H3.1 are involved in the pathogenesis of pediatric undifferentiated soft tissue sarcomas. The mechanism through which mutations lead to tumorigenesis involves altered histones methylation with gain of global H3K27 methylation, altered Polycomb repressive complex 1 (PRC1) activity, aberrant epigenetic regulation of gene expression and impaired differentiation of mesenchimal progenitor cells.MISCELLANEOUS This histone is only present in mammals and is enriched in acetylation of Lys-15 and dimethylation of Lys-10 (H3K9me2).SIMILARITY Belongs to the histone H3 family.CAUTION The original paper reporting lysine deamination at Lys-5 by LOXL2 has been retracted due to inappropriate manipulation of figure data (PubMed:22483618, PubMed:27392148). However, this modification was confirmed in a subsequent publication (PubMed:27735137). UniProt P68431 2 EQUAL 136 EQUAL Reactome Database ID Release 78 212070 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212070 Reactome R-HSA-212070 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212070.1 HIST2H3A Histone H3.2 HIST2H3C HIST2H3D Reactome DB_ID: 212281 UniProt:Q71DI3 H3C15 H3C15 HIST2H3A H3C14 H3F2 H3FM HIST2H3C H3C13 HIST2H3D FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. During nucleosome assembly the chaperone ASF1A interacts with the histone H3-H4 heterodimer.DEVELOPMENTAL STAGE Expressed during S phase, then expression strongly decreases as cell division slows down during the process of differentiation.PTM Acetylation is generally linked to gene activation. Acetylation on Lys-10 (H3K9ac) impairs methylation at Arg-9 (H3R8me2s). Acetylation on Lys-19 (H3K18ac) and Lys-24 (H3K24ac) favors methylation at Arg-18 (H3R17me). Acetylation at Lys-123 (H3K122ac) by EP300/p300 plays a central role in chromatin structure: localizes at the surface of the histone octamer and stimulates transcription, possibly by promoting nucleosome instability.PTM Citrullination at Arg-9 (H3R8ci) and/or Arg-18 (H3R17ci) by PADI4 impairs methylation and represses transcription.PTM Asymmetric dimethylation at Arg-18 (H3R17me2a) by CARM1 is linked to gene activation. Symmetric dimethylation at Arg-9 (H3R8me2s) by PRMT5 is linked to gene repression. Asymmetric dimethylation at Arg-3 (H3R2me2a) by PRMT6 is linked to gene repression and is mutually exclusive with H3 Lys-5 methylation (H3K4me2 and H3K4me3). H3R2me2a is present at the 3' of genes regardless of their transcription state and is enriched on inactive promoters, while it is absent on active promoters.PTM Methylation at Lys-5 (H3K4me), Lys-37 (H3K36me) and Lys-80 (H3K79me) are linked to gene activation. Methylation at Lys-5 (H3K4me) facilitates subsequent acetylation of H3 and H4. Methylation at Lys-80 (H3K79me) is associated with DNA double-strand break (DSB) responses and is a specific target for TP53BP1. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are linked to gene repression. Methylation at Lys-10 (H3K9me) is a specific target for HP1 proteins (CBX1, CBX3 and CBX5) and prevents subsequent phosphorylation at Ser-11 (H3S10ph) and acetylation of H3 and H4. Methylation at Lys-5 (H3K4me) and Lys-80 (H3K79me) require preliminary monoubiquitination of H2B at 'Lys-120'. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are enriched in inactive X chromosome chromatin. Monomethylation at Lys-57 (H3K56me1) by EHMT2/G9A in G1 phase promotes interaction with PCNA and is required for DNA replication.PTM Phosphorylated at Thr-4 (H3T3ph) by HASPIN during prophase and dephosphorylated during anaphase. Phosphorylation at Ser-11 (H3S10ph) by AURKB is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. In addition phosphorylation at Ser-11 (H3S10ph) by RPS6KA4 and RPS6KA5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or UV irradiation and result in the activation of genes, such as c-fos and c-jun. Phosphorylation at Ser-11 (H3S10ph), which is linked to gene activation, prevents methylation at Lys-10 (H3K9me) but facilitates acetylation of H3 and H4. Phosphorylation at Ser-11 (H3S10ph) by AURKB mediates the dissociation of HP1 proteins (CBX1, CBX3 and CBX5) from heterochromatin. Phosphorylation at Ser-11 (H3S10ph) is also an essential regulatory mechanism for neoplastic cell transformation. Phosphorylated at Ser-29 (H3S28ph) by MAP3K20 isoform 1, RPS6KA5 or AURKB during mitosis or upon ultraviolet B irradiation. Phosphorylation at Thr-7 (H3T6ph) by PRKCB is a specific tag for epigenetic transcriptional activation that prevents demethylation of Lys-5 (H3K4me) by LSD1/KDM1A. At centromeres, specifically phosphorylated at Thr-12 (H3T11ph) from prophase to early anaphase, by DAPK3 and PKN1. Phosphorylation at Thr-12 (H3T11ph) by PKN1 is a specific tag for epigenetic transcriptional activation that promotes demethylation of Lys-10 (H3K9me) by KDM4C/JMJD2C. Phosphorylation at Tyr-42 (H3Y41ph) by JAK2 promotes exclusion of CBX5 (HP1 alpha) from chromatin.PTM Monoubiquitinated by RAG1 in lymphoid cells, monoubiquitination is required for V(D)J recombination. Ubiquitinated by the CUL4-DDB-RBX1 complex in response to ultraviolet irradiation. This may weaken the interaction between histones and DNA and facilitate DNA accessibility to repair proteins.PTM Lysine deamination at Lys-5 (H3K4all) to form allysine is mediated by LOXL2. Allysine formation by LOXL2 only takes place on H3K4me3 and results in gene repression.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Butyrylation of histones marks active promoters and competes with histone acetylation. It is present during late spermatogenesis.PTM Succinylation at Lys-80 (H3K79succ) by KAT2A takes place with a maximum frequency around the transcription start sites of genes (PubMed:29211711). It gives a specific tag for epigenetic transcription activation (PubMed:29211711). Desuccinylation at Lys-123 (H3K122succ) by SIRT7 in response to DNA damage promotes chromatin condensation and double-strand breaks (DSBs) repair (PubMed:27436229).PTM Serine ADP-ribosylation constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:29480802). Serine ADP-ribosylation at Ser-11 (H3S10ADPr) is mutually exclusive with phosphorylation at Ser-11 (H3S10ph) and impairs acetylation at Lys-10 (H3K9ac) (PubMed:30257210).PTM Serotonylated by TGM2 at Gln-6 (H3Q5ser) during serotonergic neuron differentiation (PubMed:30867594). H3Q5ser is associated with trimethylation of Lys-5 (H3K4me3) and enhances general transcription factor IID (TFIID) complex-binding to H3K4me3, thereby facilitating transcription (PubMed:30867594).PTM Dopaminylated by TGM2 at Gln-6 (H3Q5dop) in ventral tegmental area (VTA) neurons (PubMed:32273471). H3Q5dop mediates neurotransmission-independent role of nuclear dopamine by regulating relapse-related transcriptional plasticity in the reward system (By similarity).PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H3 family.CAUTION The original paper reporting lysine deamination at Lys-5 by LOXL2 has been retracted due to inappropriate manipulation of figure data (PubMed:22483618, PubMed:27392148). However, this modification was confirmed in a subsequent publication (PubMed:27735137). UniProt Q71DI3 2 EQUAL 136 EQUAL Reactome Database ID Release 78 212281 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212281 Reactome R-HSA-212281 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212281.1 H3F3A Histone H3.3 Reactome DB_ID: 212295 UniProt:P84243 H3-3A H3-3A H3.3A H3F3 H3F3A PP781 H3-3B H3.3B H3F3B FUNCTION Variant histone H3 which replaces conventional H3 in a wide range of nucleosomes in active genes. Constitutes the predominant form of histone H3 in non-dividing cells and is incorporated into chromatin independently of DNA synthesis. Deposited at sites of nucleosomal displacement throughout transcribed genes, suggesting that it represents an epigenetic imprint of transcriptionally active chromatin. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. Interacts with HIRA, a chaperone required for its incorporation into nucleosomes. Interacts with ZMYND11; when trimethylated at 'Lys-36' (H3.3K36me3).DEVELOPMENTAL STAGE Expressed throughout the cell cycle independently of DNA synthesis.DOMAIN Specific interaction of trimethylated form at 'Lys-36' (H3.3K36me3) with ZMYND11 is mediated by the encapsulation of Ser-32 residue with a composite pocket formed by the tandem bromo-PWWP domains.PTM Acetylation is generally linked to gene activation. Acetylation on Lys-10 (H3K9ac) impairs methylation at Arg-9 (H3R8me2s). Acetylation on Lys-19 (H3K18ac) and Lys-24 (H3K24ac) favors methylation at Arg-18 (H3R17me). Acetylation at Lys-123 (H3K122ac) by EP300/p300 plays a central role in chromatin structure: localizes at the surface of the histone octamer and stimulates transcription, possibly by promoting nucleosome instability.PTM Citrullination at Arg-9 (H3R8ci) and/or Arg-18 (H3R17ci) by PADI4 impairs methylation and represses transcription.PTM Asymmetric dimethylation at Arg-18 (H3R17me2a) by CARM1 is linked to gene activation. Symmetric dimethylation at Arg-9 (H3R8me2s) by PRMT5 is linked to gene repression. Asymmetric dimethylation at Arg-3 (H3R2me2a) by PRMT6 is linked to gene repression and is mutually exclusive with H3 Lys-5 methylation (H3K4me2 and H3K4me3). H3R2me2a is present at the 3' of genes regardless of their transcription state and is enriched on inactive promoters, while it is absent on active promoters.PTM Specifically enriched in modifications associated with active chromatin such as methylation at Lys-5 (H3K4me), Lys-37 and Lys-80. Methylation at Lys-5 (H3K4me) facilitates subsequent acetylation of H3 and H4. Methylation at Lys-80 (H3K79me) is associated with DNA double-strand break (DSB) responses and is a specific target for TP53BP1. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me), which are linked to gene repression, are underrepresented. Methylation at Lys-10 (H3K9me) is a specific target for HP1 proteins (CBX1, CBX3 and CBX5) and prevents subsequent phosphorylation at Ser-11 (H3S10ph) and acetylation of H3 and H4. Methylation at Lys-5 (H3K4me) and Lys-80 (H3K79me) require preliminary monoubiquitination of H2B at 'Lys-120'. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are enriched in inactive X chromosome chromatin. Monomethylation at Lys-57 (H3K56me1) by EHMT2/G9A in G1 phase promotes interaction with PCNA and is required for DNA replication.PTM Phosphorylated at Thr-4 (H3T3ph) by HASPIN during prophase and dephosphorylated during anaphase. Phosphorylation at Ser-11 (H3S10ph) by AURKB is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. In addition phosphorylation at Ser-11 (H3S10ph) by RPS6KA4 and RPS6KA5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or UV irradiation and result in the activation of genes, such as c-fos and c-jun. Phosphorylation at Ser-11 (H3S10ph), which is linked to gene activation, prevents methylation at Lys-10 (H3K9me) but facilitates acetylation of H3 and H4. Phosphorylation at Ser-11 (H3S10ph) by AURKB mediates the dissociation of HP1 proteins (CBX1, CBX3 and CBX5) from heterochromatin. Phosphorylation at Ser-11 (H3S10ph) is also an essential regulatory mechanism for neoplastic cell transformation. Phosphorylated at Ser-29 (H3S28ph) by MAP3K20 isoform 1, RPS6KA5 or AURKB during mitosis or upon ultraviolet B irradiation. Phosphorylation at Thr-7 (H3T6ph) by PRKCB is a specific tag for epigenetic transcriptional activation that prevents demethylation of Lys-5 (H3K4me) by LSD1/KDM1A. At centromeres, specifically phosphorylated at Thr-12 (H3T11ph) from prophase to early anaphase, by DAPK3 and PKN1. Phosphorylation at Thr-12 (H3T11ph) by PKN1 is a specific tag for epigenetic transcriptional activation that promotes demethylation of Lys-10 (H3K9me) by KDM4C/JMJD2C. Phosphorylation at Tyr-42 (H3Y41ph) by JAK2 promotes exclusion of CBX5 (HP1 alpha) from chromatin. Phosphorylation on Ser-32 (H3S31ph) is specific to regions bordering centromeres in metaphase chromosomes.PTM Ubiquitinated. Monoubiquitinated by RAG1 in lymphoid cells, monoubiquitination is required for V(D)J recombination (By similarity).PTM Lysine deamination at Lys-5 (H3K4all) to form allysine is mediated by LOXL2. Allysine formation by LOXL2 only takes place on H3K4me3 and results in gene repression.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Butyrylation of histones marks active promoters and competes with histone acetylation. It is present during late spermatogenesis.PTM Succinylation at Lys-80 (H3K79succ) by KAT2A takes place with a maximum frequency around the transcription start sites of genes (PubMed:29211711). It gives a specific tag for epigenetic transcription activation (PubMed:29211711). Desuccinylation at Lys-123 (H3K122succ) by SIRT7 in response to DNA damage promotes chromatin condensation and double-strand breaks (DSBs) repair (PubMed:27436229).PTM Serine ADP-ribosylation constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:29480802). Serine ADP-ribosylation at Ser-11 (H3S10ADPr) is mutually exclusive with phosphorylation at Ser-11 (H3S10ph) and impairs acetylation at Lys-10 (H3K9ac) (PubMed:30257210).PTM Serotonylated by TGM2 at Gln-6 (H3Q5ser) during serotonergic neuron differentiation (PubMed:30867594). H3Q5ser is associated with trimethylation of Lys-5 (H3K4me3) and enhances general transcription factor IID (TFIID) complex-binding to H3K4me3, thereby facilitating transcription (PubMed:30867594).PTM Dopaminylated by TGM2 at Gln-6 (H3Q5dop) in ventral tegmental area (VTA) neurons (PubMed:32273471). H3Q5dop mediates neurotransmission-independent role of nuclear dopamine by regulating relapse-related transcriptional plasticity in the reward system (By similarity).PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.DISEASE H3F3A and H3F3B mutations affecting residues involved in post-translational modifications of histone H3.3 are implicated in the pathogenesis of some bone and cartilage neoplasms. Mutations have been found with high prevalence in chondroblastoma and giant cell tumors of bone, and with low frequency in osteosarcoma, conventional chondrosarcoma and clear cell chondrosarcoma. Chondroblastoma samples frequently carry a H3F3B mutation affecting residue Lys-37 (H3K36), although H3F3A is mutated in some cases. Most giant cell tumors of bone harbor H3F3A mutations affecting residue Gly-35 (H3G34).SIMILARITY Belongs to the histone H3 family.CAUTION The original paper reporting lysine deamination at Lys-5 by LOXL2 has been retracted due to inappropriate manipulation of figure data (PubMed:22483618, PubMed:27392148). However, this modification was confirmed in a subsequent publication (PubMed:27735137). UniProt P84243 2 EQUAL 136 EQUAL Reactome Database ID Release 78 212295 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212295 Reactome R-HSA-212295 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212295.1 Reactome Database ID Release 78 212293 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212293 Reactome R-HSA-212293 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212293.1 2 HIST1H4 Histone H4 HIST1H4A HIST1H4B HIST1H4C HIST1H4D HIST1H4E HIST1H4F HIST1H4H HIST1H4I HIST1H4J HIST1H4K HIST1H4L HIST2H4A HIST2H4B Reactome DB_ID: 181902 UniProt:P62805 H4C1 H4C1 H4/A H4FA HIST1H4A H4C2 H4/I H4FI HIST1H4B H4C3 H4/G H4FG HIST1H4C H4C4 H4/B H4FB HIST1H4D H4C5 H4/J H4FJ HIST1H4E H4C6 H4/C H4FC HIST1H4F H4C8 H4/H H4FH HIST1H4H H4C9 H4/M H4FM HIST1H4I H4C11 H4/E H4FE HIST1H4J H4C12 H4/D H4FD HIST1H4K H4C13 H4/K H4FK HIST1H4L H4C14 H4/N H4F2 H4FN HIST2H4 HIST2H4A H4C15 H4/O H4FO HIST2H4B H4-16 HIST4H4 FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Acetylation at Lys-6 (H4K5ac), Lys-9 (H4K8ac), Lys-13 (H4K12ac) and Lys-17 (H4K16ac) occurs in coding regions of the genome but not in heterochromatin.PTM Citrullination at Arg-4 (H4R3ci) by PADI4 impairs methylation.PTM Monomethylation and asymmetric dimethylation at Arg-4 (H4R3me1 and H4R3me2a, respectively) by PRMT1 favors acetylation at Lys-9 (H4K8ac) and Lys-13 (H4K12ac). Demethylation is performed by JMJD6. Symmetric dimethylation on Arg-4 (H4R3me2s) by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage.PTM Monomethylated, dimethylated or trimethylated at Lys-21 (H4K20me1, H4K20me2, H4K20me3) (PubMed:12086618, PubMed:15964846, PubMed:17967882). Monomethylation is performed by KMT5A/SET8 (PubMed:15964846). Dimethylation and trimethylation is performed by KMT5B and KMT5C and induces gene silencing (By similarity). Monomethylated at Lys-13 (H4K12me1) by N6AMT1; H4K12me1 modification is present at the promoters of numerous genes encoding cell cycle regulators (PubMed:31061526).PTM Phosphorylated by PAK2 at Ser-48 (H4S47ph). This phosphorylation increases the association of H3.3-H4 with the histone chaperone HIRA, thus promoting nucleosome assembly of H3.3-H4 and inhibiting nucleosome assembly of H3.1-H4.PTM Ubiquitinated by the CUL4-DDB-RBX1 complex in response to ultraviolet irradiation. This may weaken the interaction between histones and DNA and facilitate DNA accessibility to repair proteins. Monoubiquitinated at Lys-92 of histone H4 (H4K91ub1) in response to DNA damage. The exact role of H4K91ub1 in DNA damage response is still unclear but it may function as a licensing signal for additional histone H4 post-translational modifications such as H4 Lys-21 methylation (H4K20me).PTM Ufmylated; monofmylated by UFL1 at Lys-32 (H4K31Ufm1) in response to DNA damage.PTM Sumoylated, which is associated with transcriptional repression.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Butyrylation of histones marks active promoters and competes with histone acetylation.PTM Glutarylation at Lys-92 (H4K91glu) destabilizes nucleosomes by promoting dissociation of the H2A-H2B dimers from nucleosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.DISEASE Chromosomal aberrations involving HISTONE H4 is a cause of B-cell non-Hodgkin lymphomas (B-cell NHL). Translocation t(3;6)(q27;p21), with BCL6.SIMILARITY Belongs to the histone H4 family. UniProt P62805 2 EQUAL 103 EQUAL Reactome Database ID Release 78 181902 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181902 Reactome R-HSA-181902 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181902.1 2 Converted from EntitySet in Reactome Histone H2A Reactome DB_ID: 181899 H2AFB1 Histone H2A-Bbd Reactome DB_ID: 181887 UniProt:P0C5Y9 H2AB1 H2AB1 H2AFB1 FUNCTION Atypical histone H2A which can replace conventional H2A in some nucleosomes and is associated with active transcription and mRNA processing (PubMed:22795134). Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability (PubMed:15257289, PubMed:16287874, PubMed:16957777, PubMed:17591702, PubMed:17726088, PubMed:18329190, PubMed:22795134). Nucleosomes containing this histone are less rigid and organize less DNA than canonical nucleosomes in vivo (PubMed:15257289, PubMed:16957777, PubMed:17591702, PubMed:24336483). They are enriched in actively transcribed genes and associate with the elongating form of RNA polymerase (PubMed:17591702, PubMed:24753410). They associate with spliceosome components and are required for mRNA splicing (PubMed:22795134).SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. May be incorporated into a proportion of nucleosomes, replacing one or more H2A molecules.TISSUE SPECIFICITY Present in mature sperm.DOMAIN The docking domain is responsible for the weaker heterodimerization with H2B.MISCELLANEOUS In contrast to other H2A histones, it does not contain the conserved residues that are the target of post-translational modifications.SIMILARITY Belongs to the histone H2A family.CAUTION Although related to variant histone H2AB1 in mouse (AC Q9CQ70), it is unclear whether human and mouse H2AB1 proteins are involved in similar processes. In mouse, variant histone H2AB1 is specifically required to direct the transformation of dissociating nucleosomes to protamine in male germ cells during spermatogenesis. It is however unclear whether human protein, which participates in mRNA processing and is associated with active transcription, is also involved in nucleosomes to protamine replacement (PubMed:22795134). UniProt P0C5Y9 1 EQUAL 115 EQUAL Reactome Database ID Release 78 181887 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181887 Reactome R-HSA-181887 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181887.1 HIST1H2AB Reactome DB_ID: 181888 UniProt:P04908 H2AC4 H2AC4 H2AFM HIST1H2AB H2AC8 H2AFA HIST1H2AE FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Deiminated on Arg-4 in granulocytes upon calcium entry.PTM Monoubiquitination of Lys-120 (H2AK119Ub) by RING1, TRIM37 and RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. It is involved in the initiation of both imprinted and random X inactivation. Ubiquitinated H2A is enriched in inactive X chromosome chromatin. Ubiquitination of H2A functions downstream of methylation of 'Lys-27' of histone H3 (H3K27me). H2AK119Ub by RNF2/RING2 can also be induced by ultraviolet and may be involved in DNA repair. Monoubiquitination of Lys-120 (H2AK119Ub) by TRIM37 may promote transformation of cells in a number of breast cancers (PubMed:25470042). Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties by the E2 ligase UBE2N and the E3 ligases RNF8 and RNF168, leading to the recruitment of repair proteins to sites of DNA damage. Ubiquitination at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) in response to DNA damage is initiated by RNF168 that mediates monoubiquitination at these 2 sites, and 'Lys-63'-linked ubiquitin are then conjugated to monoubiquitin; RNF8 is able to extend 'Lys-63'-linked ubiquitin chains in vitro. Deubiquitinated by USP51 at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) after damaged DNA is repaired (PubMed:27083998). H2AK119Ub and ionizing radiation-induced 'Lys-63'-linked ubiquitination (H2AK13Ub and H2AK15Ub) are distinct events.PTM Phosphorylation on Ser-2 (H2AS1ph) is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1. Phosphorylation at Thr-121 (H2AT120ph) by DCAF1 is present in the regulatory region of many tumor suppresor genes and down-regulates their transcription.PTM Glutamine methylation at Gln-105 (H2AQ104me) by FBL is specifically dedicated to polymerase I. It is present at 35S ribosomal DNA locus and impairs binding of the FACT complex (PubMed:24352239).PTM Symmetric dimethylation on Arg-4 by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.MASS SPECTROMETRY Monoisotopic with N-acetylserine.SIMILARITY Belongs to the histone H2A family. UniProt P04908 2 EQUAL 130 EQUAL Reactome Database ID Release 78 181888 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181888 Reactome R-HSA-181888 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181888.1 HIST1H2AJ Histone H2A.e Reactome DB_ID: 181890 UniProt:Q99878 H2AC14 H2AC14 H2AFE HIST1H2AJ FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Deiminated on Arg-4 in granulocytes upon calcium entry.PTM Monoubiquitination of Lys-120 (H2AK119Ub) by RING1, TRIM37 and RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. It is involved in the initiation of both imprinted and random X inactivation. Ubiquitinated H2A is enriched in inactive X chromosome chromatin. Ubiquitination of H2A functions downstream of methylation of 'Lys-27' of histone H3 (H3K27me). H2AK119Ub by RNF2/RING2 can also be induced by ultraviolet and may be involved in DNA repair. Monoubiquitination of Lys-120 (H2AK119Ub) by TRIM37 may promote transformation of cells in a number of breast cancers (PubMed:25470042). Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties by the E2 ligase UBE2N and the E3 ligases RNF8 and RNF168, leading to the recruitment of repair proteins to sites of DNA damage. Ubiquitination at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) in response to DNA damage is initiated by RNF168 that mediates monoubiquitination at these 2 sites, and 'Lys-63'-linked ubiquitin are then conjugated to monoubiquitin; RNF8 is able to extend 'Lys-63'-linked ubiquitin chains in vitro. Deubiquitinated by USP51 at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) after damaged DNA is repaired (PubMed:27083998). H2AK119Ub and ionizing radiation-induced 'Lys-63'-linked ubiquitination (H2AK13Ub and H2AK15Ub) are distinct events.PTM Phosphorylation on Ser-2 (H2AS1ph) is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1. Phosphorylation at Thr-121 (H2AT120ph) by DCAF1 is present in the regulatory region of many tumor suppresor genes and down-regulates their transcription.PTM Glutamine methylation at Gln-105 (H2AQ104me) by FBL is specifically dedicated to polymerase I. It is present at 35S ribosomal DNA locus and impairs binding of the FACT complex (PubMed:24352239).PTM Symmetric dimethylation on Arg-4 by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.MASS SPECTROMETRY Monoisotopic with N-acetylserine.SIMILARITY Belongs to the histone H2A family. UniProt Q99878 2 EQUAL 128 EQUAL Reactome Database ID Release 78 181890 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181890 Reactome R-HSA-181890 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181890.1 HIST1H2AD Histone H2A.g Reactome DB_ID: 181896 UniProt:P20671 H2AC7 H2AC7 H2AFG HIST1H2AD FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Deiminated on Arg-4 in granulocytes upon calcium entry.PTM Monoubiquitination of Lys-120 (H2AK119Ub) by RING1, TRIM37 and RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. It is involved in the initiation of both imprinted and random X inactivation. Ubiquitinated H2A is enriched in inactive X chromosome chromatin. Ubiquitination of H2A functions downstream of methylation of 'Lys-27' of histone H3 (H3K27me). H2AK119Ub by RNF2/RING2 can also be induced by ultraviolet and may be involved in DNA repair. Monoubiquitination of Lys-120 (H2AK119Ub) by TRIM37 may promote transformation of cells in a number of breast cancers (PubMed:25470042). Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties by the E2 ligase UBE2N and the E3 ligases RNF8 and RNF168, leading to the recruitment of repair proteins to sites of DNA damage. Ubiquitination at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) in response to DNA damage is initiated by RNF168 that mediates monoubiquitination at these 2 sites, and 'Lys-63'-linked ubiquitin are then conjugated to monoubiquitin; RNF8 is able to extend 'Lys-63'-linked ubiquitin chains in vitro. Deubiquitinated by USP51 at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) after damaged DNA is repaired (PubMed:27083998). H2AK119Ub and ionizing radiation-induced 'Lys-63'-linked ubiquitination (H2AK13Ub and H2AK15Ub) are distinct events.PTM Phosphorylation on Ser-2 (H2AS1ph) is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1. Phosphorylation at Thr-121 (H2AT120ph) by DCAF1 is present in the regulatory region of many tumor suppresor genes and down-regulates their transcription.PTM Glutamine methylation at Gln-105 (H2AQ104me) by FBL is specifically dedicated to polymerase I. It is present at 35S ribosomal DNA locus and impairs binding of the FACT complex (PubMed:24352239).PTM Symmetric dimethylation on Arg-4 by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.MASS SPECTROMETRY Monoisotopic with N-acetylserine.SIMILARITY Belongs to the histone H2A family.CAUTION Was originally thought to originate from mouse. UniProt P20671 2 EQUAL 130 EQUAL Reactome Database ID Release 78 181896 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181896 Reactome R-HSA-181896 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181896.1 HIST1H2AC Histone H2A.l Reactome DB_ID: 181895 UniProt:Q93077 H2AC6 H2AC6 H2AFL HIST1H2AC FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Deiminated on Arg-4 in granulocytes upon calcium entry.PTM Monoubiquitination of Lys-120 (H2AK119Ub) by RING1, TRIM37 and RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. It is involved in the initiation of both imprinted and random X inactivation. Ubiquitinated H2A is enriched in inactive X chromosome chromatin. Ubiquitination of H2A functions downstream of methylation of 'Lys-27' of histone H3 (H3K27me). H2AK119Ub by RNF2/RING2 can also be induced by ultraviolet and may be involved in DNA repair. Monoubiquitination of Lys-120 (H2AK119Ub) by TRIM37 may promote transformation of cells in a number of breast cancers (PubMed:25470042). Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties by the E2 ligase UBE2N and the E3 ligases RNF8 and RNF168, leading to the recruitment of repair proteins to sites of DNA damage. Ubiquitination at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) in response to DNA damage is initiated by RNF168 that mediates monoubiquitination at these 2 sites, and 'Lys-63'-linked ubiquitin are then conjugated to monoubiquitin; RNF8 is able to extend 'Lys-63'-linked ubiquitin chains in vitro. Deubiquitinated by USP51 at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) after damaged DNA is repaired (PubMed:27083998). H2AK119Ub and ionizing radiation-induced 'Lys-63'-linked ubiquitination (H2AK13Ub and H2AK15Ub) are distinct events.PTM Phosphorylation on Ser-2 (H2AS1ph) is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1. Phosphorylation at Thr-121 (H2AT120ph) by DCAF1 is present in the regulatory region of many tumor suppresor genes and down-regulates their transcription.PTM Glutamine methylation at Gln-105 (H2AQ104me) by FBL is specifically dedicated to polymerase I. It is present at 35S ribosomal DNA locus and impairs binding of the FACT complex (PubMed:24352239).PTM Symmetric dimethylation on Arg-4 by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.MASS SPECTROMETRY Monoisotopic with N-acetylserine.SIMILARITY Belongs to the histone H2A family. UniProt Q93077 2 EQUAL 130 EQUAL Reactome Database ID Release 78 181895 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181895 Reactome R-HSA-181895 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181895.1 HIST2H2AA3 Histone H2A.o Reactome DB_ID: 181891 UniProt:Q6FI13 H2AC18 H2AC18 H2AFO HIST2H2AA HIST2H2AA3 H2AC19 HIST2H2AA4 FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Deiminated on Arg-4 in granulocytes upon calcium entry.PTM Monoubiquitination of Lys-120 (H2AK119Ub) by RING1, TRIM37 and RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. It is involved in the initiation of both imprinted and random X inactivation. Ubiquitinated H2A is enriched in inactive X chromosome chromatin. Ubiquitination of H2A functions downstream of methylation of 'Lys-27' of histone H3 (H3K27me). H2AK119Ub by RNF2/RING2 can also be induced by ultraviolet and may be involved in DNA repair. Monoubiquitination of Lys-120 (H2AK119Ub) by TRIM37 may promote transformation of cells in a number of breast cancers (PubMed:25470042). Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties by the E2 ligase UBE2N and the E3 ligases RNF8 and RNF168, leading to the recruitment of repair proteins to sites of DNA damage. Ubiquitination at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) in response to DNA damage is initiated by RNF168 that mediates monoubiquitination at these 2 sites, and 'Lys-63'-linked ubiquitin are then conjugated to monoubiquitin; RNF8 is able to extend 'Lys-63'-linked ubiquitin chains in vitro. Deubiquitinated by USP51 at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) after damaged DNA is repaired (PubMed:27083998). H2AK119Ub and ionizing radiation-induced 'Lys-63'-linked ubiquitination (H2AK13Ub and H2AK15Ub) are distinct events.PTM Phosphorylation on Ser-2 (H2AS1ph) is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1. Phosphorylation at Thr-121 (H2AT120ph) by DCAF1 is present in the regulatory region of many tumor suppresor genes and down-regulates their transcription.PTM Glutamine methylation at Gln-105 (H2AQ104me) by FBL is specifically dedicated to polymerase I. It is present at 35S ribosomal DNA locus and impairs binding of the FACT complex (PubMed:24352239).PTM Symmetric dimethylation on Arg-4 by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.MASS SPECTROMETRY Monoisotopic with N-acetylserine.SIMILARITY Belongs to the histone H2A family. UniProt Q6FI13 2 EQUAL 130 EQUAL Reactome Database ID Release 78 181891 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181891 Reactome R-HSA-181891 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181891.1 HIST2H2AC Histone H2A.q Reactome DB_ID: 181892 UniProt:Q16777 H2AC20 H2AC20 H2AFQ HIST2H2AC FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Deiminated on Arg-4 in granulocytes upon calcium entry.PTM Monoubiquitination of Lys-120 (H2AK119Ub) by RING1, TRIM37 and RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. It is involved in the initiation of both imprinted and random X inactivation. Ubiquitinated H2A is enriched in inactive X chromosome chromatin. Ubiquitination of H2A functions downstream of methylation of 'Lys-27' of histone H3 (H3K27me). H2AK119Ub by RNF2/RING2 can also be induced by ultraviolet and may be involved in DNA repair. Monoubiquitination of Lys-120 (H2AK119Ub) by TRIM37 may promote transformation of cells in a number of breast cancers (PubMed:25470042). Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties by the E2 ligase UBE2N and the E3 ligases RNF8 and RNF168, leading to the recruitment of repair proteins to sites of DNA damage. Ubiquitination at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) in response to DNA damage is initiated by RNF168 that mediates monoubiquitination at these 2 sites, and 'Lys-63'-linked ubiquitin are then conjugated to monoubiquitin; RNF8 is able to extend 'Lys-63'-linked ubiquitin chains in vitro. Deubiquitinated by USP51 at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) after damaged DNA is repaired (PubMed:27083998). H2AK119Ub and ionizing radiation-induced 'Lys-63'-linked ubiquitination (H2AK13Ub and H2AK15Ub) are distinct events.PTM Phosphorylation on Ser-2 (H2AS1ph) is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1. Phosphorylation at Thr-121 (H2AT120ph) by DCAF1 is present in the regulatory region of many tumor suppresor genes and down-regulates their transcription.PTM Symmetric dimethylation on Arg-4 by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage.PTM Glutamine methylation at Gln-105 (H2AQ104me) by FBL is specifically dedicated to polymerase I. It is present at 35S ribosomal DNA locus and impairs binding of the FACT complex (PubMed:24352239).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.MASS SPECTROMETRY Monoisotopic with N-acetylserine.SIMILARITY Belongs to the histone H2A family. UniProt Q16777 2 EQUAL 129 EQUAL Reactome Database ID Release 78 181892 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181892 Reactome R-HSA-181892 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181892.1 H2AFJ Histone H2A.J H2AJ_HUMAN Reactome DB_ID: 8862432 UniProt:Q9BTM1 H2AJ H2AJ H2AFJ FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination of Lys-120 (H2AXK119ub) gives a specific tag for epigenetic transcriptional repression. Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties (By similarity).PTM Phosphorylation on Ser-2 (H2AS1ph) is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1. Phosphorylation at Thr-121 (H2AT120ph) by DCAF1 is present in the regulatory region of many tumor suppresor genes and down-regulates their transcription (By similarity).PTM Glutamine methylation at Gln-105 (H2AQ104me) by FBL is specifically dedicated to polymerase I. It is present at 35S ribosomal DNA locus and impairs binding of the FACT complex (By similarity).SIMILARITY Belongs to the histone H2A family. UniProt Q9BTM1 2 EQUAL 129 EQUAL Reactome Database ID Release 78 8862432 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8862432 Reactome R-HSA-8862432 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8862432.2 H2AFV Histone H2A.V H2AV_HUMAN Reactome DB_ID: 8862427 UniProt:Q71UI9 H2AZ2 H2AZ2 H2AFV H2AV FUNCTION Variant histone H2A which replaces conventional H2A in a subset of nucleosomes. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. May be involved in the formation of constitutive heterochromatin. May be required for chromosome segregation during cell division (By similarity).SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. H2A or its variant H2AZ2 forms a heterodimer with H2B (By similarity).PTM Monoubiquitination of Lys-122 gives a specific tag for epigenetic transcriptional repression.PTM Acetylated on Lys-5, Lys-8 and Lys-12 during interphase. Acetylation disappears at mitosis (By similarity).MASS SPECTROMETRY Monoisotopic, not modified.SIMILARITY Belongs to the histone H2A family. UniProt Q71UI9 1 EQUAL 128 EQUAL Reactome Database ID Release 78 8862427 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8862427 Reactome R-HSA-8862427 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8862427.2 H2AFX Histone H2A.x H2a/x Reactome DB_ID: 56151 UniProt:P16104 H2AX H2AX H2AFX FUNCTION Variant histone H2A which replaces conventional H2A in a subset of nucleosomes. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. Required for checkpoint-mediated arrest of cell cycle progression in response to low doses of ionizing radiation and for efficient repair of DNA double strand breaks (DSBs) specifically when modified by C-terminal phosphorylation.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA (Probable). Interacts with numerous proteins required for DNA damage signaling and repair when phosphorylated on Ser-140 (PubMed:12419185, PubMed:12607005, PubMed:15201865). These include MDC1, TP53BP1, BRCA1 and the MRN complex, composed of MRE11, RAD50, and NBN (PubMed:12419185, PubMed:12607005, PubMed:15201865). Interaction with the MRN complex is mediated at least in part by NBN (PubMed:12419185). Also interacts with DHX9/NDHII when phosphorylated on Ser-140 and MCPH1 when phosphorylated at Ser-140 or Tyr-143 (PubMed:15613478). Interacts with ARRB2; the interaction is detected in the nucleus upon OR1D2 stimulation (PubMed:16820410). Interacts with WRAP53/TCAB1 (PubMed:26734725, PubMed:27715493).SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus protein EBNA6.DEVELOPMENTAL STAGE Synthesized in G1 as well as in S-phase.DOMAIN The [ST]-Q motif constitutes a recognition sequence for kinases from the PI3/PI4-kinase family.PTM Phosphorylated on Ser-140 (to form gamma-H2AX or H2AX139ph) in response to DNA double strand breaks (DSBs) generated by exogenous genotoxic agents and by stalled replication forks, and may also occur during meiotic recombination events and immunoglobulin class switching in lymphocytes. Phosphorylation can extend up to several thousand nucleosomes from the actual site of the DSB and may mark the surrounding chromatin for recruitment of proteins required for DNA damage signaling and repair. Widespread phosphorylation may also serve to amplify the damage signal or aid repair of persistent lesions. Phosphorylation of Ser-140 (H2AX139ph) in response to ionizing radiation is mediated by both ATM and PRKDC while defects in DNA replication induce Ser-140 phosphorylation (H2AX139ph) subsequent to activation of ATR and PRKDC. Dephosphorylation of Ser-140 by PP2A is required for DNA DSB repair. In meiosis, Ser-140 phosphorylation (H2AX139ph) may occur at synaptonemal complexes during leptotene as an ATM-dependent response to the formation of programmed DSBs by SPO11. Ser-140 phosphorylation (H2AX139ph) may subsequently occurs at unsynapsed regions of both autosomes and the XY bivalent during zygotene, downstream of ATR and BRCA1 activation. Ser-140 phosphorylation (H2AX139ph) may also be required for transcriptional repression of unsynapsed chromatin and meiotic sex chromosome inactivation (MSCI), whereby the X and Y chromosomes condense in pachytene to form the heterochromatic XY-body. During immunoglobulin class switch recombination in lymphocytes, Ser-140 phosphorylation (H2AX139ph) may occur at sites of DNA-recombination subsequent to activation of the activation-induced cytidine deaminase AICDA. Phosphorylation at Tyr-143 (H2AXY142ph) by BAZ1B/WSTF determines the relative recruitment of either DNA repair or pro-apoptotic factors. Phosphorylation at Tyr-143 (H2AXY142ph) favors the recruitment of APBB1/FE65 and pro-apoptosis factors such as MAPK8/JNK1, triggering apoptosis. In contrast, dephosphorylation of Tyr-143 by EYA proteins (EYA1, EYA2, EYA3 or EYA4) favors the recruitment of MDC1-containing DNA repair complexes to the tail of phosphorylated Ser-140 (H2AX139ph).PTM Monoubiquitination of Lys-120 (H2AXK119ub) by RING1 and RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression (By similarity). Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties by the E2 ligase UBE2N and the E3 ligases RNF8 and RNF168, leading to the recruitment of repair proteins to sites of DNA damage. Ubiquitination at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) in response to DNA damage is initiated by RNF168 that mediates monoubiquitination at these 2 sites, and 'Lys-63'-linked ubiquitin are then conjugated to monoubiquitin; RNF8 is able to extend 'Lys-63'-linked ubiquitin chains in vitro. H2AK119Ub and ionizing radiation-induced 'Lys-63'-linked ubiquitination (H2AK13Ub and H2AK15Ub) are distinct events.PTM Acetylation at Lys-37 increases in S and G2 phases. This modification has been proposed to play a role in DNA double-strand break repair (By similarity).SIMILARITY Belongs to the histone H2A family. UniProt P16104 2 EQUAL 143 EQUAL Reactome Database ID Release 78 56151 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=56151 Reactome R-HSA-56151 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-56151.1 H2AFZ Histone H2A.z Reactome DB_ID: 181897 UniProt:P0C0S5 H2AZ1 H2AZ1 H2AFZ H2AZ FUNCTION Variant histone H2A which replaces conventional H2A in a subset of nucleosomes. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. May be involved in the formation of constitutive heterochromatin. May be required for chromosome segregation during cell division.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. H2A or its variant H2AZ1 forms a heterodimer with H2B. H2AZ1 interacts with INCENP (By similarity). Interacts (via M6 cassette) with ANP32E; leading to removal of H2A.Z/H2AZ1 from the nucleosome. Heterodimer H2BC11 and H2AZ1 interacts with VPS72 (via N-terminal domain) (PubMed:26974126). Interacts with PWWP2A (PubMed:28645917). Interacts with FH (when phosphorylated by PRKDC) (PubMed:26237645).PTM Monoubiquitination of Lys-122 gives a specific tag for epigenetic transcriptional repression.PTM Acetylated on Lys-5, Lys-8, Lys-12 and Lys-14 by KAT2A; KAT2A is recruited by the XPC complex in absence of DNA damage (PubMed:31527837). Acetylated on Lys-5, Lys-8 and Lys-12 during interphase; acetylation disappears at mitosis (By similarity).PTM Monomethylated on Lys-5 and Lys-8 by SETD6. SETD6 predominantly methylates Lys-8, lys-5 being a possible secondary site.PTM Not phosphorylated.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.MASS SPECTROMETRY Monoisotopic, not modified.SIMILARITY Belongs to the histone H2A family. UniProt P0C0S5 2 EQUAL 128 EQUAL Reactome Database ID Release 78 181897 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181897 Reactome R-HSA-181897 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181897.1 Reactome Database ID Release 78 181899 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181899 Reactome R-HSA-181899 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181899.2 2 Converted from EntitySet in Reactome Histone H2B Reactome DB_ID: 181911 HIST1H2BK Histone H2B K Reactome DB_ID: 181898 UniProt:O60814 H2BC12 H2BC12 H2BFT HIRIP1 HIST1H2BK FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.FUNCTION Has broad antibacterial activity. May contribute to the formation of the functional antimicrobial barrier of the colonic epithelium, and to the bactericidal activity of amniotic fluid.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt O60814 2 EQUAL 126 EQUAL Reactome Database ID Release 78 181898 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181898 Reactome R-HSA-181898 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181898.1 HIST3H2BB Histone H2B type 12 Reactome DB_ID: 181923 UniProt:Q8N257 H2BU1 H2BU1 HIST3H2BB FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt Q8N257 2 EQUAL 126 EQUAL Reactome Database ID Release 78 181923 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181923 Reactome R-HSA-181923 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181923.1 HIST1H2BA Histone H2B, testis Reactome DB_ID: 181916 UniProt:Q96A08 H2BC1 H2BC1 HIST1H2BA TSH2B FUNCTION Variant histone specifically required to direct the transformation of dissociating nucleosomes to protamine in male germ cells (By similarity). Entirely replaces classical histone H2B prior nucleosome to protamine transition and probably acts as a nucleosome dissociating factor that creates a more dynamic chromatin, facilitating the large-scale exchange of histones (By similarity). Core component of nucleosome (By similarity). Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template (By similarity). Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability (By similarity). DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling (By similarity). Also found in fat cells, its function and the presence of post-translational modifications specific to such cells are still unclear (PubMed:21249133).SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers.TISSUE SPECIFICITY Mainly expressed in testis, and the corresponding protein is also present in mature sperm (at protein level). Also found in some fat cells.PTM Monoubiquitination at Lys-36 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-122 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Acetylated during spermatogenesis. Acetylated form is most abundant in spermatogonia compared to spermatocytes and round spermatids (By similarity).PTM Phosphorylated at Thr-117 in spermatogonia, spermatocytes and round spermatids.PTM Methylated at Lys-118 in spermatogonia, spermatocytes and round spermatids.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt Q96A08 2 EQUAL 127 EQUAL Reactome Database ID Release 78 181916 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181916 Reactome R-HSA-181916 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181916.1 HIST1H2BC Histone H2B type 1-C/E/F/G/I Reactome DB_ID: 181906 UniProt:P62807 H2BC4 H2BC4 H2BFL HIST1H2BC H2BC6 H2BFH HIST1H2BE H2BC7 H2BFG HIST1H2BF H2BC8 H2BFA HIST1H2BG H2BC10 H2BFK HIST1H2BI FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.FUNCTION Has broad antibacterial activity. May contribute to the formation of the functional antimicrobial barrier of the colonic epithelium, and to the bactericidal activity of amniotic fluid.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt P62807 2 EQUAL 126 EQUAL Reactome Database ID Release 78 181906 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181906 Reactome R-HSA-181906 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181906.1 HIST1H2BD Histone H2B.b Reactome DB_ID: 181912 UniProt:P58876 H2BC5 H2BC5 H2BFB HIRIP2 HIST1H2BD FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM ADP-ribosylated on Ser-7 in response to DNA damage.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.MISCELLANEOUS The mouse orthologous protein seems not to exist.SIMILARITY Belongs to the histone H2B family. UniProt P58876 2 EQUAL 126 EQUAL Reactome Database ID Release 78 181912 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181912 Reactome R-HSA-181912 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181912.1 HIST1H2BL Histone H2B.c Reactome DB_ID: 181920 UniProt:Q99880 H2BC13 H2BC13 H2BFC HIST1H2BL FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.PTM ADP-ribosylated on Ser-7 in response to DNA damage.SIMILARITY Belongs to the histone H2B family. UniProt Q99880 2 EQUAL 126 EQUAL Reactome Database ID Release 78 181920 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181920 Reactome R-HSA-181920 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181920.1 HIST1H2BN Histone H2B.d Reactome DB_ID: 181907 UniProt:Q99877 H2BC15 H2BC15 H2BFD HIST1H2BN FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt Q99877 2 EQUAL 126 EQUAL Reactome Database ID Release 78 181907 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181907 Reactome R-HSA-181907 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181907.1 HIST1H2BM Histone H2B.e Reactome DB_ID: 181917 UniProt:Q99879 H2BC14 H2BC14 H2BFE HIST1H2BM FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM ADP-ribosylated on Ser-7 in response to DNA damage.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt Q99879 2 EQUAL 126 EQUAL Reactome Database ID Release 78 181917 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181917 Reactome R-HSA-181917 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181917.1 HIST1H2BB Histone H2B.f Reactome DB_ID: 181903 UniProt:P33778 H2BC3 H2BC3 H2BFF HIST1H2BB FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt P33778 2 EQUAL 126 EQUAL Reactome Database ID Release 78 181903 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181903 Reactome R-HSA-181903 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181903.1 HIST1H2BH Histone H2B.j Reactome DB_ID: 181915 UniProt:Q93079 H2BC9 H2BC9 H2BFJ HIST1H2BH FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers (Probable). The octamer wraps approximately 147 bp of DNA (Probable). Found in a complex with PPAR9; DTX3L AND STAT1; the interaction is likely to induce DTX3L-mediated ubiquitination of H2BC9/H2BJ (PubMed:26479788).PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons (PubMed:16627869). Monoubiquitinated by DTX3L upon encephalomyocarditis virus (EMCV)-mediated infection (PubMed:26479788).PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt Q93079 2 EQUAL 126 EQUAL Reactome Database ID Release 78 181915 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181915 Reactome R-HSA-181915 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181915.1 HIST1H2BO Histone H2B.n Reactome DB_ID: 181910 UniProt:P23527 H2BC17 H2BC17 H2BFH H2BFN HIST1H2BO FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.MISCELLANEOUS The mouse orthologous protein seems not to exist.SIMILARITY Belongs to the histone H2B family. UniProt P23527 2 EQUAL 126 EQUAL Reactome Database ID Release 78 181910 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181910 Reactome R-HSA-181910 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181910.1 HIST2H2BE Histone H2B.q Reactome DB_ID: 181908 UniProt:Q16778 H2BC21 H2BC21 H2BFQ HIST2H2BE FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.FUNCTION Has broad antibacterial activity. May contribute to the formation of the functional antimicrobial barrier of the colonic epithelium, and to the bactericidal activity of amniotic fluid.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt Q16778 2 EQUAL 126 EQUAL Reactome Database ID Release 78 181908 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181908 Reactome R-HSA-181908 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181908.1 HIST1H2BJ Histone H2B.r Reactome DB_ID: 181900 UniProt:P06899 H2BC11 H2BC11 H2BFR HIST1H2BJ FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.FUNCTION Has broad antibacterial activity. May contribute to the formation of the functional antimicrobial barrier of the colonic epithelium, and to the bactericidal activity of amniotic fluid.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. Heterodimer H2BC11 and H2AZ1 interacts with VPS72 (via N-terminal domain) (PubMed:26974126).PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt P06899 2 EQUAL 126 EQUAL Reactome Database ID Release 78 181900 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181900 Reactome R-HSA-181900 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181900.1 H2BFS Histone H2B.s Reactome DB_ID: 181904 UniProt:P57053 H2BS1 H2BS1 H2BFS FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.FUNCTION Has broad antibacterial activity. May contribute to the formation of the functional antimicrobial barrier of the colonic epithelium, and to the bactericidal activity of amniotic fluid.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt P57053 2 EQUAL 126 EQUAL Reactome Database ID Release 78 181904 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181904 Reactome R-HSA-181904 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181904.1 Reactome Database ID Release 78 181911 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=181911 Reactome R-HSA-181911 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-181911.1 2 Reactome Database ID Release 78 427402 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=427402 Reactome R-HSA-427402 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-427402.1 INHIBITION Reactome Database ID Release 78 427398 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=427398 Reactome R-HSA-427398 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-427398.1 Chromatin (H3K9me2, 5mC):MBD2 Reactome DB_ID: 427343 MBD2 Methyl-CpG-binding domain protein 2 MBD2_HUMAN Reactome DB_ID: 427367 UniProt:Q9UBB5 MBD2 MBD2 FUNCTION Binds CpG islands in promoters where the DNA is methylated at position 5 of cytosine within CpG dinucleotides. Binds hemimethylated DNA as well. Recruits histone deacetylases and DNA methyltransferases. Acts as transcriptional repressor and plays a role in gene silencing. Functions as a scaffold protein, targeting GATAD2A and GATAD2B to chromatin to promote repression. May enhance the activation of some unmethylated cAMP-responsive promoters.SUBUNIT Heterodimer with MBD3. Component of the MeCP1 complex that contains HDAC1 and HDAC2. Binds DNMT1, MIZF, GPN1, SIN3A, GATAD2A/p66-alpha and GATAD2B/p66-beta. Interacts with DHX9. Interacts with SPHK2 (PubMed:19729656).TISSUE SPECIFICITY Highly expressed in brain, heart, kidney, stomach, testis and placenta.CAUTION Functional studies (PubMed:10050851, PubMed:10950960 and PubMed:12665568) have used a C-terminal fragment of isoform 1 which has been described originally as isoform MBD2b but cannot however be proven by supporting cDNA sequences. UniProt Q9UBB5 1 EQUAL 411 EQUAL Reactome Database ID Release 78 427367 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=427367 Reactome R-HSA-427367 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-427367.1 1 Chromatin with H3K9me2, 5mC Reactome DB_ID: 5226877 methylated DNA DNA containing 5-mC Double-Stranded DNA containing 5-methylcytosine Reactome DB_ID: 212172 Reactome Database ID Release 78 212172 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212172 Reactome R-ALL-212172 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-212172.1 ChEBI 4705 COMPOUND C02967 ChEBI 27551 1 Nucleosome with H3K9me2 Nucleosome with Deacetylated H4 and H3 Dimethylated at Lysine-9 Reactome DB_ID: 427331 2 2 2 Converted from EntitySet in Reactome Histone H3 dimethylated at lysine-9 Reactome DB_ID: 427406 Me2K10-HIST1H3A Histone H3.1 with dimethylated lysine9 (H3K9) Reactome DB_ID: 427378 10 EQUAL N6,N6-dimethyl-L-lysine MOD MOD:00084 2 EQUAL 136 EQUAL Reactome Database ID Release 78 427378 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=427378 Reactome R-HSA-427378 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-427378.1 Me2K-10-HIST2H3A Histone H3.2 with dimethylated lysine9 (H3K9) Reactome DB_ID: 427407 10 EQUAL 2 EQUAL 136 EQUAL Reactome Database ID Release 78 427407 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=427407 Reactome R-HSA-427407 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-427407.1 Me2K-10-H3F3A Histone H3.3 with dimethylated lysine9 (H3K9) Reactome DB_ID: 427324 10 EQUAL 2 EQUAL 136 EQUAL Reactome Database ID Release 78 427324 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=427324 Reactome R-HSA-427324 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-427324.1 Reactome Database ID Release 78 427406 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=427406 Reactome R-HSA-427406 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-427406.1 2 Reactome Database ID Release 78 427331 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=427331 Reactome R-HSA-427331 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-427331.1 1 Reactome Database ID Release 78 5226877 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5226877 Reactome R-HSA-5226877 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5226877.1 1 Reactome Database ID Release 78 427343 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=427343 Reactome R-HSA-427343 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-427343.1 LEFT-TO-RIGHT 2.7.11.24 Phosphorylation of UBF-1:rDNA Promoter Phosphorylation of UBF-1, bound to the promoter, activates UBF-1 and recruits SL1, and eventually polymerase. This phosphorylation of UBF-1 by Erk1, has been shown to both weaken the binding of UBF-1 to DNA and to activate transcription (the authors of the paper showing these data suggest that loosening the binding of UBF-1 with the promoter may somehow promote transcription initiation). Though not definitively worked out phosphorylation of UBF-1 by Erk1 plays a role in the activation of the UBF-1:rDNA complex. Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 29358 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 78 29358 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29358 Reactome R-ALL-29358 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29358.3 COMPOUND C00002 Phosphorylated UBF-1:rDNA promoter Reactome DB_ID: 73685 UBF-1 p-UBTF phosphorylated UBF-1 Nucleolar transcription factor 1 Upstream binding factor 1 Autoantigen NOR-90 Reactome DB_ID: 76039 phosphorylated residue MOD MOD:00696 1 EQUAL 764 EQUAL Reactome Database ID Release 78 76039 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76039 Reactome R-HSA-76039 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-76039.1 1 1 Reactome Database ID Release 78 73685 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73685 Reactome R-HSA-73685 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73685.1 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 113582 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 78 113582 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113582 Reactome R-ALL-113582 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113582.3 COMPOUND C00008 ACTIVATION phospho-ERK-1 dimer p-T202, Y204 MAPK3 dimer Reactome DB_ID: 109845 p-T202,Y204-MAPK3 p-T202,Y204-ERK-1 Mitogen-activated protein kinase 3(phosphorylated) Extracellular signal-regulated kinase 1(phosphorylated) Insulin-stimulated MAP2 kinase MAP kinase 1 phosphorylated p-T202,Y204-MAPK 1 p44-ERK1phosphorylated ERT2 phosphorylated MAP kinase isoform p44(phosphorylated) Microtubule- associated protein-2 kinase Reactome DB_ID: 112359 UniProt:P27361 MAPK3 MAPK3 ERK1 PRKM3 FUNCTION Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK1/ERK2 and MAPK3/ERK1 are the 2 MAPKs which play an important role in the MAPK/ERK cascade. They participate also in a signaling cascade initiated by activated KIT and KITLG/SCF. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. The MAPK/ERK cascade plays also a role in initiation and regulation of meiosis, mitosis, and postmitotic functions in differentiated cells by phosphorylating a number of transcription factors. About 160 substrates have already been discovered for ERKs. Many of these substrates are localized in the nucleus, and seem to participate in the regulation of transcription upon stimulation. However, other substrates are found in the cytosol as well as in other cellular organelles, and those are responsible for processes such as translation, mitosis and apoptosis. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling through the perinuclear recycling compartment (PNRC); as well as in the fragmentation of the Golgi apparatus during mitosis. The substrates include transcription factors (such as ATF2, BCL6, ELK1, ERF, FOS, HSF4 or SPZ1), cytoskeletal elements (such as CANX, CTTN, GJA1, MAP2, MAPT, PXN, SORBS3 or STMN1), regulators of apoptosis (such as BAD, BTG2, CASP9, DAPK1, IER3, MCL1 or PPARG), regulators of translation (such as EIF4EBP1) and a variety of other signaling-related molecules (like ARHGEF2, FRS2 or GRB10). Protein kinases (such as RAF1, RPS6KA1/RSK1, RPS6KA3/RSK2, RPS6KA2/RSK3, RPS6KA6/RSK4, SYK, MKNK1/MNK1, MKNK2/MNK2, RPS6KA5/MSK1, RPS6KA4/MSK2, MAPKAPK3 or MAPKAPK5) and phosphatases (such as DUSP1, DUSP4, DUSP6 or DUSP16) are other substrates which enable the propagation the MAPK/ERK signal to additional cytosolic and nuclear targets, thereby extending the specificity of the cascade.ACTIVITY REGULATION Phosphorylated by MAP2K1/MEK1 and MAP2K2/MEK2 on Thr-202 and Tyr-204 in response to external stimuli like insulin or NGF. Both phosphorylations are required for activity. This phosphorylation causes dramatic conformational changes, which enable full activation and interaction of MAPK1/ERK2 with its substrates. Dephosphorylated and inactivated by DUSP3, DUSP6 and DUSP9.SUBUNIT Binds both upstream activators and downstream substrates in multimolecular complexes. Found in a complex with at least BRAF, HRAS, MAP2K1/MEK1, MAPK3 and RGS14 (By similarity). Interacts with ADAM15, ARRB2, CANX, DAPK1 (via death domain), HSF4, IER3, MAP2K1/MEK1, MORG1, NISCH, and SGK1. Interacts with PEA15 and MKNK2 (By similarity). MKNK2 isoform 1 binding prevents from dephosphorylation and inactivation (By similarity). Interacts with TPR. Interacts with CDKN2AIP. Interacts with HSF1 (via D domain and preferentially with hyperphosphorylated form); this interaction occurs upon heat shock (PubMed:10747973). Interacts with CAVIN4 (By similarity). Interacts with GIT1; this interaction is necessary for MAPK3 localization to focal adhesions (By similarity). Interacts with ZNF263 (PubMed:32051553).SUBUNIT (Microbial infection) Binds to HIV-1 Nef through its SH3 domain. This interaction inhibits its tyrosine-kinase activity.DOMAIN The TXY motif contains the threonine and tyrosine residues whose phosphorylation activates the MAP kinases.PTM Phosphorylated upon KIT and FLT3 signaling (By similarity). Dually phosphorylated on Thr-202 and Tyr-204, which activates the enzyme. Ligand-activated ALK induces tyrosine phosphorylation. Dephosphorylated by PTPRJ at Tyr-204.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. MAP kinase subfamily. UniProt P27361 202 EQUAL O-phospho-L-threonine MOD MOD:00047 204 EQUAL O4'-phospho-L-tyrosine MOD MOD:00048 2 EQUAL 379 EQUAL Reactome Database ID Release 78 112359 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=112359 Reactome R-HSA-112359 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-112359.1 2 Reactome Database ID Release 78 109845 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=109845 Reactome R-HSA-109845 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-109845.1 GENE ONTOLOGY GO:0004707 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 78 164955 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164955 Reactome Database ID Release 78 73722 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73722 Reactome R-HSA-73722 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73722.3 11741541 Pubmed 2001 An immediate response of ribosomal transcription to growth factor stimulation in mammals is mediated by ERK phosphorylation of UBF. Stefanovsky, VY Pelletier, G Hannan, R Gagnon-Kugler, T Rothblum, LI Moss, T Mol Cell 8:1063-73 Reactome Database ID Release 78 73728 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73728 Reactome R-HSA-73728 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73728.2 GENE ONTOLOGY GO:0006361 gene ontology term for cellular process MI MI:0359 RNA Polymerase I Transcription Initiation During initiation the double-stranded DNA must be melted and transcription begins. SL1 forms and interacts with UBF-1 and the rDNA promoter. It is this platform that will recruit active RNA polymerase I to the SL1:phosphorlated UBF-1:rDNA promoter complex.<p>Mammalian rRNA genes are preceded by a terminator element that is recognized by the SL1 complex. This SL1 modulated acetylation of the basal Pol I transcription machinery has functional consequences suggesting that the reversible acetylation may be one way to regulate rDNA transcription. Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 LEFT-TO-RIGHT Formation of SL1 Human SL1 is a four subunit complex composed of the TATA-binding protein (TBP) and three TBP-associated factors (TAFs): TAF(1)110, TAF(1)63, and TAF(1)48. Note that none of these three TAFs for Pol I show any homology to the Pol II or Pol III TAFs. TAFs SL1 is a species specific factor. TAF1C TAF(1)110 TATA box binding protein TBP-associated factor, RNA polymerase I, C, 110kDa Reactome DB_ID: 73687 UniProt:Q15572 TAF1C TAF1C FUNCTION Component of the transcription factor SL1/TIF-IB complex, which is involved in the assembly of the PIC (preinitiation complex) during RNA polymerase I-dependent transcription. The rate of PIC formation probably is primarily dependent on the rate of association of SL1/TIF-IB with the rDNA promoter. SL1/TIF-IB is involved in stabilization of nucleolar transcription factor 1/UBTF on rDNA. Formation of SL1/TIF-IB excludes the association of TBP with TFIID subunits. Recruits RNA polymerase I to the rRNA gene promoter via interaction with RRN3.SUBUNIT Component of the transcription factor SL1/TIF-IB complex, composed of TBP and at least TAF1A, TAF1B, TAF1C and TAF1D. In the complex interacts directly with TBP, TAF1A and TAF1B. Interaction of the SL1/TIF-IB subunits with TBP excludes interaction of TBP with the transcription factor IID (TFIID) subunits. Interacts with MYC and RRN3. Interacts with p53/TP53; the interaction prevents the association of SL1/TIF-IB with UBTF and represses RNA polymerase I transcription. UniProt Q15572 1 EQUAL 869 EQUAL Reactome Database ID Release 78 73687 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73687 Reactome R-HSA-73687 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73687.1 TAF1B TAF(1)68 Reactome DB_ID: 73691 UniProt:Q53T94 TAF1B TAF1B FUNCTION Component of RNA polymerase I core factor complex that acts as a GTF2B/TFIIB-like factor and plays a key role in multiple steps during transcription initiation such as pre-initiation complex (PIC) assembly and postpolymerase recruitment events in polymerase I (Pol I) transcription. Binds rDNA promoters and plays a role in Pol I recruitment as a component of the SL1/TIF-IB complex and, possibly, directly through its interaction with RRN3.SUBUNIT Interacts with FLNA (via N-terminus) (By similarity). Component of the transcription factor SL1/TIF-IB complex, composed of TBP and at least TAF1A, TAF1B, TAF1C and TAF1D. In the complex interacts directly with TBP, TAF1A and TAF1C. Interaction of the SL1/TIF-IB subunits with TBP excludes interaction of TBP with the transcription factor IID (TFIID) subunits. Interacts with TBP and RRN3.DOMAIN Although it shares weak sequence similarity with GTF2B/TFIIB, displays a similar subdomain organization as GTF2B/TFIIB, with a N-terminal zinc finger, a connecting region (composed of B-reader and B-linker regions), followed by 2 cyclin folds. The RRN7-type zinc finger plays an essential postrecruitment role in Pol I transcription at a step preceding synthesis of the first 40 nucleotides (PubMed:21921198 and PubMed:21921199).SIMILARITY Belongs to the RRN7/TAF1B family. UniProt Q53T94 1 EQUAL 588 EQUAL Reactome Database ID Release 78 73691 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73691 Reactome R-HSA-73691 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73691.1 TBP TATA box binding protein (Transcription initiation factor TFIID) (TATA-box factor) (TATA sequence-binding protein) (TBP) TATA-box binding protein TATA-box factor TATA binding factor TATA sequence-binding protein Transcription initiation factor TFIID TBP subunit Reactome DB_ID: 83718 UniProt:P20226 TBP TBP GTF2D1 TF2D TFIID FUNCTION General transcription factor that functions at the core of the DNA-binding multiprotein factor TFIID (PubMed:2374612, PubMed:2363050, PubMed:2194289, PubMed:9836642, PubMed:27193682). Binding of TFIID to the TATA box is the initial transcriptional step of the pre-initiation complex (PIC), playing a role in the activation of eukaryotic genes transcribed by RNA polymerase II (PubMed:2374612, PubMed:2363050, PubMed:2194289, PubMed:9836642, PubMed:27193682). Component of a BRF2-containing transcription factor complex that regulates transcription mediated by RNA polymerase III (PubMed:26638071). Component of the transcription factor SL1/TIF-IB complex, which is involved in the assembly of the PIC (pre-initiation complex) during RNA polymerase I-dependent transcription (PubMed:15970593). The rate of PIC formation probably is primarily dependent on the rate of association of SL1 with the rDNA promoter. SL1 is involved in stabilization of nucleolar transcription factor 1/UBTF on rDNA.SUBUNIT Binds DNA as monomer (PubMed:2374612, PubMed:2194289). Belongs to the TFIID complex together with the TBP-associated factors (TAFs) (PubMed:9836642, PubMed:27007846). Part of a TFIID-containing RNA polymerase II pre-initiation complex that is composed of TBP and at least GTF2A1, GTF2A2, GTF2E1, GTF2E2, GTF2F1, GTF2H2, GTF2H3, GTF2H4, GTF2H5, GTF2B, TCEA1, ERCC2, ERCC3, TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:27007846). Component of the transcription factor SL1/TIF-IB complex, composed of TBP and at least TAF1A, TAF1B, TAF1C and TAF1D (PubMed:7801123). Association of TBP to form either TFIID or SL1/TIF-IB appears to be mutually exclusive (PubMed:7801123). Interacts with TAF1A, TAF1B and TAF1C (PubMed:7801123). Interacts with TFIIB, NCOA6, DRAP1, DR1 and ELF3 (PubMed:10567404, PubMed:10391676, PubMed:11461703). Interacts with SPIB, SNAPC1, SNAPC2 and SNAPC4 (PubMed:10196196, PubMed:12621023). Interacts with UTF1 (PubMed:9748258). Interacts with BRF2; this interaction promotes recruitment of BRF2 to TATA box-containing promoters (PubMed:11564744, PubMed:26638071). Interacts with UBTF (PubMed:7982918). Interacts with GPBP1 (By similarity). Interacts with CITED2 (By similarity). Interacts with ATF7IP (Probable). Interacts with LLPH (By similarity). Interacts with HSF1 (via transactivation domain) (PubMed:11005381). Interacts with GTF2B (via C-terminus); this interaction with promoter-bound TBP guides RNA polymerase II into the pre-initiation complex (PIC) (PubMed:8504927). Interacts with PAX5 (PubMed:10197586).SUBUNIT (Microbial infection) Interacts with HIV-1 Tat.SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 ICP4.SUBUNIT (Microbial infection) Interacts with herpes simplex virus 2 ICP4.SUBUNIT (Microbial infection) Interacts with human adenovirus E1A protein; this interaction probably disrupts the TBP-TATA complex.TISSUE SPECIFICITY Widely expressed, with levels highest in the testis and ovary.POLYMORPHISM The poly-Gln region of TBP is highly polymorphic (25 to 42 repeats) in normal individuals and is expanded to about 47-63 repeats in spinocerebellar ataxia 17 (SCA17) patients.SIMILARITY Belongs to the TBP family. UniProt P20226 1 EQUAL 339 EQUAL Reactome Database ID Release 78 83718 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=83718 Reactome R-HSA-83718 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-83718.1 TAF1A TAF(1)48 TATA box binding protein TBP-associated factor, RNA polymerase I, A, 48kD Reactome DB_ID: 73689 UniProt:Q15573 TAF1A TAF1A FUNCTION Component of the transcription factor SL1/TIF-IB complex, which is involved in the assembly of the PIC (pre-initiation complex) during RNA polymerase I-dependent transcription. The rate of PIC formation probably is primarily dependent on the rate of association of SL1/TIF-IB with the rDNA promoter. SL1/TIF-IB is involved in stabilization of nucleolar transcription factor 1/UBTF on rDNA. Formation of SL1/TIF-IB excludes the association of TBP with TFIID subunits.SUBUNIT Component of the transcription factor SL1/TIF-IB complex, composed of TBP and at least TAF1A, TAF1B, TAF1C and TAF1D. In the complex interacts directly with TBP, TAF1A and TAF1B. Interaction of the SL1/TIF-IB subunits with TBP excludes interaction of TBP with the transcription factor IID (TFIID) subunits. Interacts with UBFT. Interacts with CEBPA (isoform 1 and isoform 4) (PubMed:20075868). UniProt Q15573 1 EQUAL 450 EQUAL Reactome Database ID Release 78 73689 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73689 Reactome R-HSA-73689 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73689.1 TAF1D TATA box-binding protein-associated factor RNA polymerase I subunit D TAF1D_HUMAN Reactome DB_ID: 5138533 UniProt:Q9H5J8 TAF1D TAF1D JOSD3 FUNCTION Component of the transcription factor SL1/TIF-IB complex, which is involved in the assembly of the PIC (preinitiation complex) during RNA polymerase I-dependent transcription. The rate of PIC formation probably is primarily dependent on the rate of association of SL1/TIF-IB with the rDNA promoter. SL1/TIF-IB is involved in stabilization of nucleolar transcription factor 1/UBTF on rDNA. Formation of SL1/TIF-IB excludes the association of TBP with TFIID subunits.SUBUNIT Component of the transcription factor SL1/TIF-IB complex, composed of TBP and at least TAF1A, TAF1B, TAF1C and TAF1D. Interacts with UBTF. UniProt Q9H5J8 1 EQUAL 278 EQUAL Reactome Database ID Release 78 5138533 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5138533 Reactome R-HSA-5138533 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5138533.1 SL1 Reactome DB_ID: 73692 1 1 1 1 1 Reactome Database ID Release 78 73692 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73692 Reactome R-HSA-73692 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73692.1 Reactome Database ID Release 78 73729 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73729 Reactome R-HSA-73729 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73729.2 1547496 Pubmed 1992 The TATA-binding protein and associated factors are integral components of the RNA polymerase I transcription factor, SL1. Comai, L Tanese, N Tjian, R Cell 68:965-76 2805069 Pubmed 1989 Molecular mechanisms governing species-specific transcription of ribosomal RNA. Bell, SP Pikaard, CS Reeder, RH Tjian, R Cell 59:489-97 17318177 Pubmed 2007 A novel TBP-associated factor of SL1 functions in RNA polymerase I transcription Gorski, Julia J Pathak, Shalini Panov, Kostya Kasciukovic, Taciana Panova, Tanya Russell, Jackie Zomerdijk, Joost C B M EMBO J. 26:1560-8 7801123 Pubmed 1995 Reconstitution of transcription factor SL1: exclusive binding of TBP by SL1 or TFIID subunits. Comai, L Zomerdijk, JC Beckmann, H Zhou, S Tjian, R Science 266:1966-72 LEFT-TO-RIGHT 2.3.1 Acetylation of SL1 Acetylation of the TAFI63 subunit of SL1 by PCAF stimulates the association of TAFI63 with DNA and stimulates pol I transcription in vitro. Conversely, deacetylation by the NAD+-dependent deacetylase Sir2 represses pol I transcription. Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 Ac-CoA Acetyl coenzyme A acetyl-CoA Reactome DB_ID: 113560 acetyl-CoA(4-) [ChEBI:57288] acetyl-CoA(4-) acetyl-CoA 3'-phosphonatoadenosine 5'-(3-{(3R)-4-[(3-{[2-(acetylsulfanyl)ethyl]amino}-3-oxopropyl)amino]-3-hydroxy-2,2-dimethyl-4-oxobutyl} diphosphate) acetyl-coenzyme A(4-) acetyl-CoA tetraanion AcCoA(4-) ChEBI CHEBI:57288 Reactome Database ID Release 78 113560 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113560 Reactome R-ALL-113560 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113560.4 COMPOUND C00024 Acetylated SL1 Reactome DB_ID: 73693 1 1 1 1 Ac-TAF1B acetylated TAF(1)68 Reactome DB_ID: 5138530 N6-acetyl-L-lysine MOD MOD:00064 1 EQUAL 588 EQUAL Reactome Database ID Release 78 5138530 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5138530 Reactome R-HSA-5138530 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5138530.1 1 Reactome Database ID Release 78 73693 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73693 Reactome R-HSA-73693 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73693.1 CoA CoA-SH coenzyme A Reactome DB_ID: 2485002 coenzyme A(4-) [ChEBI:57287] coenzyme A(4-) 3'-phosphonatoadenosine 5'-{3-[(3R)-3-hydroxy-2,2-dimethyl-4-oxo-4-({3-oxo-3-[(2-sulfanylethyl)amino]propyl}amino)butyl] diphosphate} CoA ChEBI CHEBI:57287 Reactome Database ID Release 78 2485002 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2485002 Reactome R-ALL-2485002 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-2485002.4 COMPOUND C00010 ACTIVATION Converted from EntitySet in Reactome PCAF Reactome DB_ID: 350078 PCAF KAT2B PCAF_HUMAN Histone acetyltransferase PCAF Reactome DB_ID: 352430 UniProt:Q92831 KAT2B KAT2B PCAF FUNCTION Functions as a histone acetyltransferase (HAT) to promote transcriptional activation (PubMed:8945521). Has significant histone acetyltransferase activity with core histones (H3 and H4), and also with nucleosome core particles (PubMed:8945521). Also acetylates non-histone proteins, such as ACLY, PLK4, RRP9/U3-55K and TBX5 (PubMed:9707565, PubMed:10675335, PubMed:27796307, PubMed:23932781, PubMed:26867678, PubMed:29174768). Inhibits cell-cycle progression and counteracts the mitogenic activity of the adenoviral oncoprotein E1A (PubMed:8684459). Acts as a circadian transcriptional coactivator which enhances the activity of the circadian transcriptional activators: NPAS2-ARNTL/BMAL1 and CLOCK-ARNTL/BMAL1 heterodimers (PubMed:14645221). Involved in heart and limb development by mediating acetylation of TBX5, acetylation regulating nucleocytoplasmic shuttling of TBX5 (PubMed:29174768). Acts as a negative regulator of centrosome amplification by mediating acetylation of PLK4 (PubMed:27796307). Acetylates RRP9/U3-55K, a core subunit of the U3 snoRNP complex, impairing pre-rRNA processing (PubMed:26867678). Also acetylates spermidine (PubMed:27389534).FUNCTION (Microbial infection) In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes.ACTIVITY REGULATION Activated in vitro by very low concentrations of spermidine, but inhibited at spermidine concentrations higher than 4 uM. The activating effect of low spermidine concentrations may be mediated by N(8)-acetylspermidine produced by KAT2B/P/CAF itself acting as a positive feedback loop.SUBUNIT Interacts with SIRT1. Interacts (unsumoylated form) with NR2C1; the interaction promotes transactivation activity (By similarity). Interacts with EP300, CREBBP and DDX17. Interacts with NCOA1 and NCOA3. Component of a large chromatin remodeling complex, at least composed of MYSM1, KAT2B/PCAF, RBM10 and KIF11/TRIP5. Interacts with NR2C2 (hypophosphorylated and unsumoylated form); the interaction promotes the transactivation activity of NR2C2. Interacts with KLF1; the interaction does not acetylate KLF1 and there is no enhancement of its transactivational activity. Interacts with NFE4. Interacts with MECOM. Interacts with E2F1; the interaction acetylates E2F1 augmenting its DNA-binding and transcriptional activity. Interacts with NPAS2, ARNTL/BMAL1 and CLOCK. Interacts with BCAS3. Interacts with CEBPB (PubMed:17301242). Interacts with NR4A3 (By similarity). Interacts with NFATC2 (By similarity). Interacts with TBX5 (PubMed:29174768). Interacts with PLK4 (PubMed:27796307). Interacts with RB1; this interaction leads to RB1 acetylation (By similarity).SUBUNIT (Microbial infection) Interacts with and acetylates HIV-1 Tat.SUBUNIT (Microbial infection) Interacts with HTLV-1 Tax.TISSUE SPECIFICITY Ubiquitously expressed but most abundant in heart and skeletal muscle. Also expressed in the skin, in keratinocytes (at protein level) (PubMed:20940255).DEVELOPMENTAL STAGE Up-regulated during keratinocyte differentiation (at protein level).DOMAIN (Microbial infection) The bromodomain mediates binding to HIV-1 Tat.DISEASE Defects in KAT2B has been found in a patient with isolated coloboma, a defect of the eye characterized by the absence of ocular structures due to abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). Isolated colobomas may be associated with an abnormally small eye (microphthalmia) or small cornea.SIMILARITY Belongs to the acetyltransferase family. GCN5 subfamily. UniProt Q92831 1 EQUAL 832 EQUAL Reactome Database ID Release 78 352430 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=352430 Reactome R-HSA-352430 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-352430.1 GCN5 KAT2A Histone acetyltransferase KAT2A KAT2A_HUMAN Reactome DB_ID: 3006516 UniProt:Q92830 KAT2A KAT2A GCN5 GCN5L2 FUNCTION Protein lysine acyltransferase that can act as a acetyltransferase, glutaryltransferase or succinyltransferase, depending on the context (PubMed:29211711). Acts as a histone lysine succinyltransferase: catalyzes succinylation of histone H3 on 'Lys-79' (H3K79succ), with a maximum frequency around the transcription start sites of genes (PubMed:29211711). Succinylation of histones gives a specific tag for epigenetic transcription activation (PubMed:29211711). Association with the 2-oxoglutarate dehydrogenase complex, which provides succinyl-CoA, is required for histone succinylation (PubMed:29211711). In different complexes, functions either as an acetyltransferase (HAT) or as a succinyltransferase: in the SAGA and ATAC complexes, acts as a histone acetyltransferase (PubMed:17301242, PubMed:19103755, PubMed:29211711). Has significant histone acetyltransferase activity with core histones, but not with nucleosome core particles (PubMed:17301242, PubMed:19103755). Acetylation of histones gives a specific tag for epigenetic transcription activation (PubMed:17301242, PubMed:19103755, PubMed:29211711). Recruited by the XPC complex at promoters, where it specifically mediates acetylation of histone variant H2A.Z.1/H2A.Z, thereby promoting expression of target genes (PubMed:29973595, PubMed:31527837). Involved in long-term memory consolidation and synaptic plasticity: acts by promoting expression of a hippocampal gene expression network linked to neuroactive receptor signaling (By similarity). Acts as a positive regulator of T-cell activation: upon TCR stimulation, recruited to the IL2 promoter following interaction with NFATC2 and catalyzes acetylation of histone H3 at 'Lys-9' (H3K9ac), leading to promote IL2 expression (By similarity). Required for growth and differentiation of craniofacial cartilage and bone by regulating acetylation of histone H3 at 'Lys-9' (H3K9ac) (By similarity). Regulates embryonic stem cell (ESC) pluripotency and differentiation (By similarity). Also acetylates non-histone proteins, such as CEBPB, PLK4 and TBX5 (PubMed:17301242, PubMed:27796307, PubMed:29174768). Involved in heart and limb development by mediating acetylation of TBX5, acetylation regulating nucleocytoplasmic shuttling of TBX5 (PubMed:29174768). Acts as a negative regulator of centrosome amplification by mediating acetylation of PLK4 (PubMed:27796307). Also acts as a histone glutaryltransferase: catalyzes glutarylation of histone H4 on 'Lys-91' (H4K91glu), a mark that destabilizes nucleosomes by promoting dissociation of the H2A-H2B dimers from nucleosomes (PubMed:31542297).FUNCTION (Microbial infection) In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes.SUBUNIT Homooligomer; may form a tetramer of homodimers (PubMed:30109122). Interacts with EP300, CREBBP and ADA2. Component of the TFTC-HAT complex, at least composed of TAF5L, TAF6L, TAF3, TADA3L, SUPT3H/SPT3, TAF2/TAFII150, TAF4/TAFII135, TAF5/TAFII100, KAT2A/GCN5L2, TAF10 and TRRAP (PubMed:10373431, PubMed:10611234, PubMed:11438666). Component of the STAGA transcription coactivator-HAT complex, at least composed of SUPT3H, KAT2A, SUPT7L, TAF5L, TAF6L, TADA3L, TAD1L, TAF10, TAF12, TRRAP and TAF9 (PubMed:18206972). The STAGA core complex is associated with a subcomplex required for histone deubiquitination composed of ATXN7L3, ENY2 and USP22 (PubMed:18206972). Component of the ADA2A-containing complex (ATAC), composed of KAT14, KAT2A, TADA2L, TADA3L, ZZ3, MBIP, WDR5, YEATS2, CCDC101 and DR1 (PubMed:19103755). In the complex, it probably interacts directly with KAT14, MBIP and WDR5 (PubMed:19103755). Interacts with PML (By similarity). Interacts with CEBPB (PubMed:17301242). Interacts with TACC1, TACC2 and TACC3 (PubMed:14767476). Interacts with RELA (By similarity). Interacts with NFATC2 (By similarity). Interacts with TBX5 (PubMed:29174768). Interacts with PLK4 (PubMed:27796307). Associates with the 2-oxoglutarate dehydrogenase complex (PubMed:29211711). Interacts with XPC; leading to KAT2A recruitment to promoters and subsequent acetylation of histones (PubMed:29973595, PubMed:31527837). Interacts with ERCC3/XPB; leading to KAT2A recruitment to promoters and subsequent acetylation of histones (PubMed:30894545).SUBUNIT (Microbial infection) Interacts with and acetylates HIV-1 Tat.TISSUE SPECIFICITY Expressed in all tissues tested, with most abundant expression in ovary.DOMAIN Loop3 is required for substrate specificity and adopts different structural conformations in succinyl-CoA-bound and acetyl-CoA-bound forms. Tyr-645 has an important role in the selective binding of succinyl-CoA over acetyl-CoA.SIMILARITY Belongs to the acetyltransferase family. GCN5 subfamily.CAUTION According to a report, has weak protein acyltransferase activity compared to protein acetyltransferase activity (PubMed:27377381). These conclusions are however not supported by subsequent studies (PubMed:29211711, PubMed:31542297). UniProt Q92830 1 EQUAL 837 EQUAL Reactome Database ID Release 78 3006516 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3006516 Reactome R-HSA-3006516 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3006516.1 Reactome Database ID Release 78 350078 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=350078 Reactome R-HSA-350078 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-350078.1 GENE ONTOLOGY GO:0016407 Reactome Database ID Release 78 109690 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=109690 Reactome Database ID Release 78 73736 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73736 Reactome R-HSA-73736 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73736.2 11250901 Pubmed 2001 Acetylation of TAF(I)68, a subunit of TIF-IB/SL1, activates RNA polymerase I transcription. Muth, V Nadaud, S Grummt, I Voit, Renate EMBO J 20:1353-62 LEFT-TO-RIGHT Recruitment of Acetylated SL1 to phosUBF-1:rDNA Promoter Human SL1 does not bind to DNA itself, rather it is recruited to the rDNA promoter through a physical interaction with UBF-1. Phosphorylation of UBF-1 within the carboxy-terminal region is required for SL1 binding. SL1 consists of TATA-binding protein (TBP) and three associated factors (TAFIs). SL1 has no sequence-specific DNA binding activity its recruitment to the promoter being mediated by specific interactions with UBF. Once bound the SL1 complex makes direct contact with the DNA promoter and guides promoter-specific initiation. <p>Studies to identify the mechanistic relationship between SL1 and UBF-1 have indicated that the interaction between UBF-1 and SL1 is regulated by tumor suppressor proteins such as Rb and P53, although it has also been proposed that Rb prevents UBF-1 from binding to DNA itself. Knockdown of CSB reduces recruitment of SL1 and RNA Polymerase I to active rRNA genes. Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 Acetylayed SL1:PhosUBF-1:rDNA promoter Reactome DB_ID: 73694 1 1 Reactome Database ID Release 78 73694 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73694 Reactome R-HSA-73694 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73694.1 Reactome Database ID Release 78 73739 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73739 Reactome R-HSA-73739 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73739.4 7491500 Pubmed 1996 Coactivator and promoter-selective properties of RNA polymerase I TAFs. Beckmann, H Chen, JL O'Brien, T Tjian, R Science 270:1506-9 10082553 Pubmed 1999 Recruitment of TATA-binding protein-TAFI complex SL1 to the human ribosomal DNA promoter is mediated by the carboxy-terminal activation domain of upstream binding factor (UBF) and is regulated by UBF phosphorylation. Tuan, JC Zhai, W Comai, L Mol Cell Biol 19:2872-9 10913176 Pubmed 2000 Repression of RNA polymerase I transcription by the tumor suppressor p53. Zhai, W Comai, L Mol Cell Biol 20:5930-8 11042686 Pubmed 2000 Rb and p130 regulate RNA polymerase I transcription: Rb disrupts the interaction between UBF and SL-1. Hannan, KM Hannan, RD Smith, SD Jefferson, LS Lun, M Rothblum, LI Oncogene 19:4988-99 11486020 Pubmed 2001 Overlapping functions of the pRb family in the regulation of rRNA synthesis. Ciarmatori, S Scott, PH Sutcliffe, JE McLees, A Alzuherri, HM Dannenberg, JH te Riele, H Grummt, I Voit, Renate White, RJ Mol Cell Biol 21:5806-14 ACTIVATION Reactome Database ID Release 78 427325 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=427325 Reactome R-HSA-427325 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-427325.1 TTF-I:Sal Box:CSB:G9a:NuRD Reactome DB_ID: 427352 CSB dimer ERCC6 dimer Reactome DB_ID: 5365864 ERCC6 CSB protein Excision repair protein ERCC-6 (Cockayne syndrome protein CSB) DNA excision repair protein ERCC-6 Cockayne syndrome protein CSB Reactome DB_ID: 54429 UniProt:Q03468 ERCC6 ERCC6 CSB FUNCTION Essential factor involved in transcription-coupled nucleotide excision repair which allows RNA polymerase II-blocking lesions to be rapidly removed from the transcribed strand of active genes (PubMed:20541997, PubMed:26620705, PubMed:16246722). Upon DNA-binding, it locally modifies DNA conformation by wrapping the DNA around itself, thereby modifying the interface between stalled RNA polymerase II and DNA (PubMed:15548521). It is required for transcription-coupled repair complex formation (PubMed:16916636). It recruits the CSA complex (DCX(ERCC8) complex), nucleotide excision repair proteins and EP300 to the sites of RNA polymerase II-blocking lesions (PubMed:16916636). Plays an important role in regulating the choice of the DNA double-strand breaks (DSBs) repair pathway and G2/M checkpoint activation; DNA-dependent ATPase activity is essential for this function (PubMed:25820262). Regulates the DNA repair pathway choice by inhibiting non-homologous end joining (NHEJ), thereby promoting the homologous recombination (HR)-mediated repair of DSBs during the S/G2 phases of the cell cycle (PubMed:25820262). Mediates the activation of the ATM- and CHEK2-dependent DNA damage responses thus preventing premature entry of cells into mitosis following the induction of DNA DSBs (PubMed:25820262). Acts as a chromatin remodeler at DSBs; DNA-dependent ATPase-dependent activity is essential for this function. Remodels chromatin by evicting histones from chromatin flanking DSBs, limiting RIF1 accumulation at DSBs thereby promoting BRCA1-mediated HR (PubMed:29203878). Required for stable recruitment of ELOA and CUL5 to DNA damage sites (PubMed:28292928). Involved in UV-induced translocation of ERCC8 to the nuclear matrix (PubMed:26620705). Essential for neuronal differentiation and neuritogenesis; regulates transcription and chromatin remodeling activities required during neurogenesis (PubMed:24874740).SUBUNIT Homodimer (PubMed:16128801, PubMed:15548521). Binds DNA (PubMed:15548521). Interacts with ERCC8 (PubMed:16751180). Interacts with RNA polymerase II; interaction is enhanced by UV irradiation (PubMed:26620705). Component of the B-WICH complex, at least composed of SMARCA5/SNF2H, BAZ1B/WSTF, SF3B1, DEK, MYO1C, ERCC6, MYBBP1A and DDX21 (PubMed:16603771). Interacts with KIAA1530/UVSSA (PubMed:22466612). Interacts with ELOA and CUL5; the interaction is induced by DNA damaging agents or by inhibitors of RNA polymerase II elongation (PubMed:28292928). Interacts (via WHD region) with RIF1 (PubMed:29203878). Interacts with SMARCC2/BAF170, SMARCB1/BAF47 and the neuron-specific chromatin remodeling complex (nBAF complex)(PubMed:24874740). Interacts with ERCC5/XPG (via C-terminus); the interaction stimulates ERCC6/CSB binding to the DNA repair bubble and ERCC6/CSB ATPase activity (PubMed:16246722). May form a complex composed of RNA polymerase II, ERCC6/CSB and ERCC5/XPG which associates with the DNA repair bubble during transcription-coupled nucleotide excision repair (PubMed:16246722). Interacts with CAND1, CSTF1, DDX3X, DDX5, DDX17, DDX23, DHX36, HDAC1, HNRNPU, MTA2, PRPF3, PSMD3, RBBP4, SFPQ, SMARCA1, SMARCA2, TOP1, USP7, XRCC5, COPS3, COPS4, COPS6, DDX1, DDX41, GATAD2A, GATAD2B, PRPF4, PSMC5, SF3B2, CTR9, NONO, PSMD12 and TOP2A (PubMed:26030138).DOMAIN A C-terminal ubiquitin-binding domain (UBD) is essential for transcription-coupled nucleotide excision repair activity, interaction with RNA polymerase II, association with chromatin after UV irradiation and for mediating the UV-induced translocation of ERRC8 to the nuclear matrix.DOMAIN The N-terminal domain exerts an inhibitory effect on the helicase ATP-binding domain in such a manner that its ATPase activity is restricted (PubMed:29203878). Phosphorylation at Ser-10 and Ser-158 promotes the intramolecular interaction of the N-terminal domain with the helicase ATP-binding domain, thereby probably releasing the inhibitory effect of the N-terminal domain on its ATPase activity (PubMed:29203878).PTM Phosphorylated in a cell cycle-dependent manner at Ser-158 by cyclin A-CDK2 and at Ser-10 by ATM in response to DNA damage (PubMed:29203878). Phosphorylation at these two sites promotes the intramolecular interaction of the N-terminal domain with the helicase ATP-binding domain, thereby probably releasing the inhibitory effect of the N-terminal domain on its ATPase activity (PubMed:29203878). Phosphorylation is essential for its chromatin remodeling activity (PubMed:29203878).PTM Ubiquitinated at the C-terminus. Ubiquitination by the CSA complex leads to ERCC6 proteasomal degradation in a UV-dependent manner. Stabilized following interaction with KIAA1530/UVSSA, which promotes recruitment of deubiquitinating enzyme USP7, leading to deubiquitination of ERCC6 thereby preventing UV-induced degradation of ERCC6 by the proteasome.PTM Sumoylation at Lys-205 in an UV-radiation-dependent manner is essential for its transcription-coupled nucleotide excision repair activity.SIMILARITY Belongs to the SNF2/RAD54 helicase family. UniProt Q03468 1 EQUAL 1493 EQUAL Reactome Database ID Release 78 54429 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=54429 Reactome R-HSA-54429 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-54429.1 2 Reactome Database ID Release 78 5365864 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5365864 Reactome R-HSA-5365864 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5365864.1 1 G9a EHMT2 Histone Methyltransferase G9a Histone-lysine N-methyltransferase, H3 lysine-9 specific 3 KMT1C Reactome DB_ID: 212151 UniProt:Q96KQ7 EHMT2 EHMT2 BAT8 C6orf30 G9A KMT1C NG36 FUNCTION Histone methyltransferase that specifically mono- and dimethylates 'Lys-9' of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin. H3K9me represents a specific tag for epigenetic transcriptional repression by recruiting HP1 proteins to methylated histones. Also mediates monomethylation of 'Lys-56' of histone H3 (H3K56me1) in G1 phase, leading to promote interaction between histone H3 and PCNA and regulating DNA replication. Also weakly methylates 'Lys-27' of histone H3 (H3K27me). Also required for DNA methylation, the histone methyltransferase activity is not required for DNA methylation, suggesting that these 2 activities function independently. Probably targeted to histone H3 by different DNA-binding proteins like E2F6, MGA, MAX and/or DP1. May also methylate histone H1. In addition to the histone methyltransferase activity, also methylates non-histone proteins: mediates dimethylation of 'Lys-373' of p53/TP53. Also methylates CDYL, WIZ, ACIN1, DNMT1, HDAC1, ERCC6, KLF12 and itself.SUBUNIT Heterodimer; heterodimerizes with EHMT1/GLP (PubMed:16702210). Interacts with GFI1B and WIZ (PubMed:16688220, PubMed:16702210). Part of the E2F6.com-1 complex in G0 phase composed of E2F6, MGA, MAX, TFDP1, CBX3, BAT8, EHMT1, RING1, RNF2, MBLR, L3MBTL2 and YAF2 (PubMed:12004135). Part of a complex composed of TRIM28, HDAC1, HDAC2 and EHMT2 (PubMed:21549307). Interacts with UHRF1 (PubMed:19056828). Interacts with CDYL (PubMed:19061646). Interacts with REST only in the presence of CDYL (PubMed:19061646). Part of a complex containing at least CDYL, REST, WIZ, SETB1, EHMT1 and EHMT2 (PubMed:19061646). Interacts with PRDM9 and CDYL; interaction only takes place when PRDM9 is bound to hotspot DNA (By similarity).TISSUE SPECIFICITY Expressed in all tissues examined, with high levels in fetal liver, thymus, lymph node, spleen and peripheral blood leukocytes and lower level in bone marrow.DOMAIN The SET domain mediates interaction with WIZ.DOMAIN The ANK repeats bind H3K9me1 and H3K9me2.DOMAIN In the pre-SET domain, Cys residues bind 3 zinc ions that are arranged in a triangular cluster; some of these Cys residues contribute to the binding of two zinc ions within the cluster.PTM Methylated at Lys-185; automethylated.SIMILARITY Belongs to the class V-like SAM-binding methyltransferase superfamily. Histone-lysine methyltransferase family. Suvar3-9 subfamily.CAUTION While NG36 and G9a were originally thought to derive from 2 separate genes, all G9A transcripts also contain the in frame coding sequence of NG36.CAUTION It is uncertain whether Met-1 or Met-21 is the initiator methionine. UniProt Q96KQ7 1 EQUAL 1210 EQUAL Reactome Database ID Release 78 212151 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212151 Reactome R-HSA-212151 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212151.1 1 TTF-I:Sal Box Reactome DB_ID: 74977 TTF1 TTF-1 Reactome DB_ID: 74974 UniProt:Q15361 TTF1 TTF1 FUNCTION Multifunctional nucleolar protein that terminates ribosomal gene transcription, mediates replication fork arrest and regulates RNA polymerase I transcription on chromatin. Plays a dual role in rDNA regulation, being involved in both activation and silencing of rDNA transcription. Interaction with BAZ2A/TIP5 recovers DNA-binding activity.SUBUNIT Oligomer. The oligomeric structure enables to interact simultaneously with two separate DNA fragments. Interacts with BAZ2A/TIP5. Interacts with CAVIN1.DOMAIN The N-terminal region (NRD) inhibits DNA-binding via its interaction with the C-terminal region. UniProt Q15361 1 EQUAL 905 EQUAL Reactome Database ID Release 78 74974 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74974 Reactome R-HSA-74974 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74974.1 1 Sal Box Reactome DB_ID: 74975 NCBI Nucleotide:U13369 45S pre-rRNA gene Human ribosomal DNA 45S pre-rRNA gene NCBI Nucleotide U13369 Reactome Database ID Release 78 74975 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74975 Reactome R-HSA-74975 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74975.1 1 Reactome Database ID Release 78 74977 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74977 Reactome R-HSA-74977 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74977.1 1 NuRD complex Reactome DB_ID: 4657018 RBBP4 RbAp48 CAF1C Reactome DB_ID: 212223 UniProt:Q09028 RBBP4 RBBP4 RBAP48 FUNCTION Core histone-binding subunit that may target chromatin assembly factors, chromatin remodeling factors and histone deacetylases to their histone substrates in a manner that is regulated by nucleosomal DNA. Component of several complexes which regulate chromatin metabolism. These include the chromatin assembly factor 1 (CAF-1) complex, which is required for chromatin assembly following DNA replication and DNA repair; the core histone deacetylase (HDAC) complex, which promotes histone deacetylation and consequent transcriptional repression; the nucleosome remodeling and histone deacetylase complex (the NuRD complex), which promotes transcriptional repression by histone deacetylation and nucleosome remodeling; the PRC2 complex, which promotes repression of homeotic genes during development; and the NURF (nucleosome remodeling factor) complex.SUBUNIT Interacts with SUV39H1 and HDAC7 (By similarity). Binds directly to helix 1 of the histone fold of histone H4, a region that is not accessible when H4 is in chromatin (PubMed:8858152, PubMed:9427644). Subunit of the chromatin assembly factor 1 (CAF-1) complex, which is composed of RBBP4, CHAF1B and CHAF1A (PubMed:8858152). Subunit of the core histone deacetylase (HDAC) complex, which is composed of HDAC1, HDAC2, RBBP4 and RBBP7 (PubMed:9150135). The core HDAC complex associates with SIN3A, ARID4B/SAP180, SAP18, SAP30, SAP130, SUDS3/SAP45 and possibly ARID4A/RBP1 and ING1 to form the SIN3 HDAC complex (PubMed:9150135, PubMed:9651585, PubMed:11118440, PubMed:11784859). The core HDAC complex may also associate with MTA2, MBD3, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylase complex (the NuRD complex) (PubMed:9790534, PubMed:10444591, PubMed:11102443). The NuRD complex may also interact with MBD3L1 and MBD3L2 (PubMed:15456747, PubMed:15701600). Interacts with MTA1 (PubMed:12920132). Component of the PRC2 complex, which consists of the core subunits EED, EZH1 or EZH2, SUZ12, and RBBP4, and various combinations of accessory subunits including AEBP2, JARID2, PHF19, MTF2 and EPOP (PubMed:12435631, PubMed:12351676, PubMed:29499137, PubMed:31959557). Forms a monomeric PRC2.2 (class 2) complex consisting of at least SUZ12, RBBP4, AEBP2 and JARID2 (PubMed:29499137). Forms a dimeric PRC2.1 (class 1, PRC-PCL) complex consisting of at least SUZ12, RBBP4, and PHF19; PHF19 stabilizes the dimeric structure which enhances PRC2 interaction with chromatin (PubMed:31959557). Part of the nucleosome remodeling factor (NURF) complex which consists of SMARCA1; BPTF; RBBP4 and RBBP7 (PubMed:14609955). Interacts with the viral protein-binding domain of the retinoblastoma protein (RB1) (PubMed:7503932, PubMed:10734134). Interacts with SPEN/MINT (PubMed:11331609). Interacts with BRCA1 (PubMed:10220405). Interacts with CREBBP, and this interaction may be enhanced by the binding of phosphorylated CREB1 to CREBBP (PubMed:10866654). Component of the DREAM complex (also named LINC complex) at least composed of E2F4, E2F5, LIN9, LIN37, LIN52, LIN54, MYBL1, MYBL2, RBL1, RBL2, RBBP4, TFDP1 and TFDP2 (PubMed:17671431, PubMed:17531812). The complex exists in quiescent cells where it represses cell cycle-dependent genes (PubMed:17671431, PubMed:17531812). It dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL2 (PubMed:17671431, PubMed:17531812). Interacts with PHF6 (PubMed:24554700). Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1 (By similarity). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the WD repeat RBAP46/RBAP48/MSI1 family. UniProt Q09028 2 EQUAL 425 EQUAL Reactome Database ID Release 78 212223 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212223 Reactome R-HSA-212223 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212223.1 1 Converted from EntitySet in Reactome MTA1, MTA2, MTA3 Reactome DB_ID: 4657019 MTA1 Metastasis-associated protein MTA1 MTA1_HUMAN Reactome DB_ID: 3465550 UniProt:Q13330 MTA1 MTA1 FUNCTION Transcriptional coregulator which can act as both a transcriptional corepressor and coactivator. As a part of the histone-deacetylase multiprotein complex (NuRD), regulates transcription of its targets by modifying the acetylation status of the target chromatin and cofactor accessibility to the target DNA. In conjunction with other components of NuRD, acts as a transcriptional corepressor of BRCA1, ESR1, TFF1 and CDKN1A. Acts as a transcriptional coactivator of BCAS3, PAX5 and SUMO2, independent of the NuRD complex. Stimulates the expression of WNT1 by inhibiting the expression of its transcriptional corepressor SIX3. Regulates p53-dependent and -independent DNA repair processes following genotoxic stress. Regulates the stability and function of p53/TP53 by inhibiting its ubiquitination by COP1 and MDM2 thereby regulating the p53-dependent DNA repair. Plays an important role in tumorigenesis, tumor invasion, and metastasis. Involved in the epigenetic regulation of ESR1 expression in breast cancer in a TFAP2C, IFI16 and HDAC4/5/6-dependent manner. Plays a role in the regulation of the circadian clock and is essential for the generation and maintenance of circadian rhythms under constant light and for normal entrainment of behavior to light-dark (LD) cycles. Positively regulates the CLOCK-ARNTL/BMAL1 heterodimer mediated transcriptional activation of its own transcription and the transcription of CRY1. Regulates deacetylation of ARNTL/BMAL1 by regulating SIRT1 expression, resulting in derepressing CRY1-mediated transcription repression. Isoform Short binds to ESR1 and sequesters it in the cytoplasm and enhances its non-genomic responses. With TFCP2L1, promotes establishment and maintenance of pluripotency in embryonic stem cells (ESCs) and inhibits endoderm differentiation (By similarity).SUBUNIT Component of the nucleosome-remodeling and histone-deacetylase multiprotein complex (NuRD). Interacts with HDAC1 and ITGB3BP/CENPR. Binds to CSNK1G2 in the cytoplasm. Interacts with NACC2. Interacts with ARNTL/BMAL1 and CLOCK. Interacts with EP300, TFAP2C, IFI16, TPR, HDAC2, UBE2I/UBC9, PIAS1, PIAS3, PIAS4, p53/TP53, MDM2, COP1, SUMO1, SUMO2, SENP1 and SENP2. Interacts with SIX3; facilitates the binding of SIX3 to the core DNA motif of SIX3 promoter (By similarity). Interacts with TFCP2L1; which is indispensable for TFCP2L1-mediated self-renewal-promoting effect and endoderm-inhibiting action (By similarity).TISSUE SPECIFICITY Widely expressed. High expression in brain, liver, kidney, and cardiac muscle, ovaries, adrenal glands and virgin mammary glands. Higher in tumors than in adjacent normal tissue from the same individual. Up-regulated in a wide variety of cancers including breast, liver, ovarian, and colorectal cancer and its expression levels are closely correlated with tumor aggressiveness and metastasis.DEVELOPMENTAL STAGE Highly expressed in metastatic cells.DOMAIN Isoform Short contains a Leu-Arg-Ile-Leu-Leu motif (ER binding motif).PTM Phosphorylation by CSNK1G2/CK1 triggered by estrogen enhances corepression of estrogen receptor (ER).PTM Acetylation is essential for its transcriptional coactivator activity.PTM Sumoylation positively regulates its transcriptional corepressor activity but does not affect the protein stability. Sumoylated preferentially by SUMO2 or SUMO3 than SUMO1. Sumoylation is enhanced by PIAS1/3/4 and preferentially sumoylated by SUMO2 in the presence of PIAS1/3/4. Desumoylated by SENP1.PTM Ubiquitinated by COP1, which leads to proteasomal degradation. UniProt Q13330 1 EQUAL 715 EQUAL Reactome Database ID Release 78 3465550 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3465550 Reactome R-HSA-3465550 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3465550.1 MTA2 Metastasis-associated protein MTA2 MTA2_HUMAN Reactome DB_ID: 4657009 UniProt:O94776 MTA2 MTA2 MTA1L1 PID FUNCTION May be involved in the regulation of gene expression as repressor and activator. The repression might be related to covalent modification of histone proteins.SUBUNIT Component of the nucleosome-remodeling and histone-deacetylase multiprotein complex (NuRD) (By similarity). Interacts with HDAC7 and MBD3 (By similarity). Interacts with p53/TP53 (PubMed:11099047). Interacts with MINT (PubMed:11331609). Interacts with PIMREG (PubMed:18757745). Interacts with NACC2 (PubMed:22926524). Interacts with ERCC6 (PubMed:26030138).TISSUE SPECIFICITY Widely expressed. UniProt O94776 1 EQUAL 668 EQUAL Reactome Database ID Release 78 4657009 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4657009 Reactome R-HSA-4657009 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4657009.1 MTA3 Metastasis-associated protein MTA3 MTA3_HUMAN Reactome DB_ID: 4657013 UniProt:Q9BTC8 MTA3 MTA3 KIAA1266 FUNCTION Plays a role in maintenance of the normal epithelial architecture through the repression of SNAI1 transcription in a histone deacetylase-dependent manner, and thus the regulation of E-cadherin levels. Contributes to transcriptional repression by BCL6.SUBUNIT Component of the nucleosome-remodeling and histone-deacetylase multiprotein complex (NuRD). Interacts with BCL6. Interacts with NACC2.TISSUE SPECIFICITY Expressed in germinal centers of lymphoid tissues. No expression in nonepithelial cells.INDUCTION By estrogen. UniProt Q9BTC8 1 EQUAL 594 EQUAL Reactome Database ID Release 78 4657013 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4657013 Reactome R-HSA-4657013 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4657013.1 Reactome Database ID Release 78 4657019 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4657019 Reactome R-HSA-4657019 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4657019.1 1 Converted from EntitySet in Reactome (GATAD2A, GATAD2B) Reactome DB_ID: 4657014 GATAD2A Transcriptional repressor p66-alpha P66A_HUMAN Reactome DB_ID: 3702077 UniProt:Q86YP4 GATAD2A GATAD2A FUNCTION Transcriptional repressor. Enhances MBD2-mediated repression. Efficient repression requires the presence of GATAD2B.SUBUNIT Interacts with MBD2 and MBD3 (PubMed:12183469, PubMed:16415179, PubMed:21490301). Interaction with MBD2 is required for the enhancement of MBD2-mediated repression and for targeting to the chromatin (PubMed:12183469, PubMed:16415179, PubMed:21490301). Component of the MeCP1 histone deacetylase complex (PubMed:21490301). Interacts with histone tails, including that of histones H2A, H2B, H3 and H4 (PubMed:16415179). This interaction is reduced by histone acetylation (PubMed:16415179). Interacts with ERCC6 (PubMed:26030138).TISSUE SPECIFICITY Ubiquitous, both in fetal and adult tissues.DOMAIN Both CR1 and CR2 regions are required for speckled nuclear localization. UniProt Q86YP4 1 EQUAL 633 EQUAL Reactome Database ID Release 78 3702077 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3702077 Reactome R-HSA-3702077 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3702077.1 GATAD2B Transcriptional repressor p66-beta P66B_HUMAN Reactome DB_ID: 3702079 UniProt:Q8WXI9 GATAD2B GATAD2B KIAA1150 FUNCTION Transcriptional repressor. Enhances MBD2-mediated repression. Efficient repression requires the presence of GATAD2A. Targets MBD3 to discrete loci in the nucleus. May play a role in synapse development.SUBUNIT Interacts with MBD2 and MBD3 (PubMed:11756549, PubMed:12183469, PubMed:16415179). Interaction with MBD2 is required for the enhancement of MBD2-mediated repression and for targeting to the chromatin (PubMed:11756549, PubMed:12183469, PubMed:16415179). Component of the MeCP1 histone deacetylase complex (PubMed:11756549). Interacts with histone tails, including that of histones H2A, H2B, H3 and H4 (PubMed:16415179). Interacts with ERCC6 (PubMed:26030138).TISSUE SPECIFICITY Widely expressed.DOMAIN Both CR1 and CR2 regions are required for speckled nuclear localization. UniProt Q8WXI9 1 EQUAL 593 EQUAL Reactome Database ID Release 78 3702079 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3702079 Reactome R-HSA-3702079 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3702079.1 Reactome Database ID Release 78 4657014 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4657014 Reactome R-HSA-4657014 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4657014.1 1 HDAC1:HDAC2 Reactome DB_ID: 4657004 HDAC2 HDA2_HUMAN Histone deacetylase 2 Reactome DB_ID: 205135 UniProt:Q92769 HDAC2 HDAC2 FUNCTION Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Forms transcriptional repressor complexes by associating with MAD, SIN3, YY1 and N-COR. Interacts in the late S-phase of DNA-replication with DNMT1 in the other transcriptional repressor complex composed of DNMT1, DMAP1, PCNA, CAF1. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. May be involved in the transcriptional repression of circadian target genes, such as PER1, mediated by CRY1 through histone deacetylation. Involved in MTA1-mediated transcriptional corepression of TFF1 and CDKN1A.SUBUNIT Part of the core histone deacetylase (HDAC) complex composed of HDAC1, HDAC2, RBBP4 and RBBP7. The core complex associates with MTA2, MBD3, MTA1L1, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylation (NuRD) complex, or with SIN3, SAP18 and SAP30 to form the SIN3 HDAC complex. Component of a RCOR/GFI/KDM1A/HDAC complex. Component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B, KDM1A, RCOR1 and PHF21A. The BHC complex may also contain ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I. Part of a complex containing the core histones H2A, H2B, H3 and H4, DEK and unphosphorylated DAXX. Part of a complex containing ATR and CHD4. Forms a heterologous complex at least with YY1. Component of a mSin3A corepressor complex that contains SIN3A, SAP130, SUDS3, ARID4B, HDAC1 and HDAC2. Part of a complex composed of TRIM28, HDAC1, HDAC2 and EHMT2. Part of a complex containing at least CDYL, MIER1, MIER2, HDAC1 and HDAC2. Component of a histone deacetylase complex containing DNTTIP1, ZNF541, HDAC1 and HDAC2 (PubMed:21573134). Forms a complex comprising APPL1, RUVBL2, APPL2, CTNNB1 and HDAC1 (PubMed:19433865). Interacts with SPHK2 (PubMed:19729656). Interacts directly with GFI1 and GFI1B. Interacts with SNW1, HDAC7, PRDM6, SAP30, SETDB1 and SUV39H1. Interacts with the MACROH2A1 (via the non-histone region). Interacts with ATR, CBFA2T3, DNMT1, MINT, HDAC10, HCFC1, NRIP1, KDM4A and PELP1. Interacts with CHFR and SAP30L. Interacts (CK2 phosphorylated form) with SP3. Interacts with TSHZ3 (via its N-terminus). Interacts with APEX1; the interaction is not dependent on the acetylated status of APEX1. Interacts with PIMREG. Interacts with BCL6 (non-acetylated form). Interacts with CRY1, INSM1 and ZNF431. Interacts with NACC2. Interacts with MTA1, with a preference for sumoylated MTA1. Interacts with SIX3 (By similarity). Interacts with BEND3. Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression (PubMed:32051553).TISSUE SPECIFICITY Widely expressed; lower levels in brain and lung.PTM S-nitrosylated by GAPDH. In neurons, S-Nitrosylation at Cys-262 and Cys-274 does not affect the enzyme activity but abolishes chromatin-binding, leading to increases acetylation of histones and activate genes that are associated with neuronal development. In embryonic cortical neurons, S-Nitrosylation regulates dendritic growth and branching.SIMILARITY Belongs to the histone deacetylase family. HD type 1 subfamily. UniProt Q92769 1 EQUAL 488 EQUAL Reactome Database ID Release 78 205135 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=205135 Reactome R-HSA-205135 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-205135.1 1 HDAC1 HDA1_HUMAN Histone deacetylase 1 Reactome DB_ID: 205021 UniProt:Q13547 HDAC1 HDAC1 RPD3L1 FUNCTION Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Deacetylates SP proteins, SP1 and SP3, and regulates their function. Component of the BRG1-RB1-HDAC1 complex, which negatively regulates the CREST-mediated transcription in resting neurons. Upon calcium stimulation, HDAC1 is released from the complex and CREBBP is recruited, which facilitates transcriptional activation. Deacetylates TSHZ3 and regulates its transcriptional repressor activity. Deacetylates 'Lys-310' in RELA and thereby inhibits the transcriptional activity of NF-kappa-B. Deacetylates NR1D2 and abrogates the effect of KAT5-mediated relieving of NR1D2 transcription repression activity. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Involved in CIART-mediated transcriptional repression of the circadian transcriptional activator: CLOCK-ARNTL/BMAL1 heterodimer. Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex or CRY1 through histone deacetylation.SUBUNIT Part of the core histone deacetylase (HDAC) complex composed of HDAC1, HDAC2, RBBP4 and RBBP7. The core complex associates with MTA2, MBD2, MBD3, MTA1L1, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylation (NuRD) complex, or with SIN3, SAP18 and SAP30 to form the SIN3 HDAC complex. Component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B/BRAF35, KDM1A, RCOR1/CoREST and PHF21A/BHC80. The BHC complex may also contain ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I. Component of a mSin3A corepressor complex that contains SIN3A, SAP130, SUDS3/SAP45, ARID4B/SAP180, HDAC1 and HDAC2. Found in a trimeric complex with APBB1 and TSHZ3; the interaction between HDAC1 and APBB1 is mediated by TSHZ3. Component of a RCOR/GFI/KDM1A/HDAC complex. Part of a complex composed of TRIM28, HDAC1, HDAC2 and EHMT2. Part of a complex containing at least CDYL, MIER1, MIER2, HDAC1 and HDAC2. The large PER complex involved in the histone deacetylation is composed of at least HDAC1, PER2, SFPQ and SIN3A. Associates with the 9-1-1 complex; interacts with HUS1. Found in a complex with DNMT3A and HDAC7. Interacts with the non-histone region of MACROH2A1. Interacts with TRIM28; the interaction recruits HDAC1 to E2F1 and inhibits its acetylation. Interacts with SP1; the interaction deacetylates SP1 and regulates its transcriptional activity. Interacts with SP3; the interaction deacetylates SP3 and regulates its transcriptional activity. In vitro, C(18) ceramides increase this interaction and the subsequent SP3 deacetylation and SP3-mediated repression of the TERT promoter. Interacts with TSHZ3 (via N-terminus); the interaction is direct. Interacts with APEX1; the interaction is not dependent on the acetylated status of APEX1. Interacts with C10orf90/FATS (via its N-terminal); the interaction prevents binding of HDAC1 to CDKN1A/p21 and facilitates the acetylation and stabilization of CDKN1A/p21. Interacts with CDKN1A/p21. Interacts with CDK5 complexed to CDK5R1 (p25). Interacts directly with GFI1 and GFI1B. Interacts with NR1D2 (via C-terminus). Interacts with TSC22D3 isoform 1; this interaction affects HDAC1 activity on MYOG promoter and thus inhibits MYOD1 transcriptional activity. Interacts with BAZ2A/TIP5, BANP, BCL6, BCOR, BHLHE40/DEC1, BRMS1, BRMS1L, CBFA2T3, CHFR, CIART, CRY1, DAXX, DDIT3/CHOP, DDX5, DNMT1, E4F1, EP300, HCFC1, HDAC9, INSM1, NFE4, NR4A2/NURR1, MIER1, KDM4A, KDM5B, KLF1, MINT, NRIP1, PCAF, PHB2, PRDM6, PRDM16, RB1, RERE, SAMSN1, SAP30L, SETDB1, SMAD3, SMARCA4/BRG1, SMYD2, SUV39H1, TGIF, TGIF2, TRAF6, UHRF1, UHRF2, ZMYND15, ZNF431 and ZNF541. Interacts with KDM5A (By similarity). Interacts with DNTTIP1 (PubMed:25653165). Identified in a histone deacetylase complex that contains DNTTIP1, HDAC1 and MIDEAS; this complex assembles into a tetramer that contains four copies of each protein chain (PubMed:25653165). Interacts with CCAR2 (PubMed:21030595). Interacts with PPHLN1 (PubMed:17963697). Found in a complex with YY1, SIN3A and GON4L (By similarity). Interacts with CHD4 (PubMed:27616479). Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1. Interacts with SIN3A (By similarity). Interacts with DHX36; this interaction occurs in a RNA-dependent manner (PubMed:18279852). Interacts with ZBTB7A (PubMed:25514493). Interacts with SMAD4; positively regulated by ZBTB7A (PubMed:25514493). Interacts with PACS2 (PubMed:29656858). Forms a complex comprising APPL1, RUVBL2, APPL2, CTNNB1 and HDAC2 (PubMed:19433865). Interacts with ZNF638 (PubMed:30487602). Interacts with SPHK2 (PubMed:19729656). Interacts with ERCC6 (PubMed:26030138). Interacts with NSD2 (By similarity).TISSUE SPECIFICITY Ubiquitous, with higher levels in heart, pancreas and testis, and lower levels in kidney and brain.PTM Sumoylated on Lys-444 and Lys-476; which promotes enzymatic activity. Desumoylated by SENP1.PTM Phosphorylation on Ser-421 and Ser-423 promotes enzymatic activity and interactions with NuRD and SIN3 complexes. Phosphorylated by CDK5.PTM Ubiquitinated by CHFR, leading to its degradation by the proteasome. Ubiquitinated by KCTD11, leading to proteasomal degradation.SIMILARITY Belongs to the histone deacetylase family. HD type 1 subfamily. UniProt Q13547 1 EQUAL 482 EQUAL Reactome Database ID Release 78 205021 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=205021 Reactome R-HSA-205021 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-205021.1 1 Reactome Database ID Release 78 4657004 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4657004 Reactome R-HSA-4657004 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4657004.1 1 Converted from EntitySet in Reactome Mi-2 Reactome DB_ID: 4657021 CHD4 Chromodomain-helicase-DNA-binding protein 4 CHD4_HUMAN Reactome DB_ID: 3702078 UniProt:Q14839 CHD4 CHD4 FUNCTION Component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin by deacetylating histones.SUBUNIT Interacts with KLF1; the interaction depends on sumoylation of KLF1, and leads to its transcriptional repression (By similarity). Interacts directly with IKFZ1 in the NuRD complex. Central component of the nucleosome remodeling and histone deacetylase (NuRD) repressor complex (PubMed:9804427, PubMed:10204490, PubMed:15454082). Part of a complex containing ATR and HDAC2 (PubMed:10545197). Interacts with TRIM27 (PubMed:14530259). Interacts with ZGPAT; the interaction is direct (PubMed:19644445). Interacts with BCL6 (PubMed:15454082). Interacts with BRD4 (PubMed:21555454). Interacts with PCNT (PubMed:17626165). Interacts with SETX (PubMed:23149945). Interacts with HDAC1 (PubMed:27616479).MISCELLANEOUS One of the main antigens reacting with anti-MI-2 positive sera of dermatomyositis.SIMILARITY Belongs to the SNF2/RAD54 helicase family. UniProt Q14839 1 EQUAL 1912 EQUAL Reactome Database ID Release 78 3702078 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3702078 Reactome R-HSA-3702078 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3702078.1 CHD3 Chromodomain-helicase-DNA-binding protein 3 CHD3_HUMAN Reactome DB_ID: 4657012 UniProt:Q12873 CHD3 CHD3 FUNCTION Component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin by deacetylating histones (PubMed:9804427, PubMed:30397230). Involved in transcriptional repressiobn as part of the NuRD complex (PubMed:27068747). Required for anchoring centrosomal pericentrin in both interphase and mitosis, for spindle organization and centrosome integrity (PubMed:17626165).SUBUNIT Central component of the nucleosome remodeling and histone deacetylase (NuRD) repressive complex (PubMed:9804427, PubMed:27068747). Interacts with TRIM28 (PubMed:11230151). Interacts with SERBP1 (PubMed:12505151). Interacts (via its C-terminal) with HABP4 (PubMed:12505151). Interacts with PCNT; the interaction regulates centrosome integrity (PubMed:17626165). Interacts with ZBED1/hDREF (PubMed:27068747).TISSUE SPECIFICITY Widely expressed.PTM Sumoylation at Lys-1971 results in dissociation from chromatin and suppression of transcriptional repression.MISCELLANEOUS One of the main antigens reacting with anti-MI-2 positive sera of dermatomyositis.SIMILARITY Belongs to the SNF2/RAD54 helicase family. UniProt Q12873 1 EQUAL 2000 EQUAL Reactome Database ID Release 78 4657012 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4657012 Reactome R-HSA-4657012 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4657012.1 Reactome Database ID Release 78 4657021 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4657021 Reactome R-HSA-4657021 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4657021.1 1 RBBP7 RbAp46 Reactome DB_ID: 212227 UniProt:Q16576 RBBP7 RBBP7 RBAP46 FUNCTION Core histone-binding subunit that may target chromatin remodeling factors, histone acetyltransferases and histone deacetylases to their histone substrates in a manner that is regulated by nucleosomal DNA. Component of several complexes which regulate chromatin metabolism. These include the type B histone acetyltransferase (HAT) complex, which is required for chromatin assembly following DNA replication; the core histone deacetylase (HDAC) complex, which promotes histone deacetylation and consequent transcriptional repression; the nucleosome remodeling and histone deacetylase complex (the NuRD complex), which promotes transcriptional repression by histone deacetylation and nucleosome remodeling; and the PRC2/EED-EZH2 complex, which promotes repression of homeotic genes during development; and the NURF (nucleosome remodeling factor) complex.SUBUNIT Binds directly to helix 1 of the histone fold of histone H4, a region that is not accessible when H4 is in chromatin (PubMed:18571423). Subunit of the type B histone acetyltransferase (HAT) complex, composed of RBBP7 and HAT1. Subunit of the core histone deacetylase (HDAC) complex, which is composed of HDAC1, HDAC2, RBBP4 and RBBP7. The core HDAC complex associates with SIN3A, ARID4B/SAP180, SAP18, SAP30, SAP130, SUDS3/SAP45 and possibly ARID4A/RBP1 and ING1 to form the SIN3 HDAC complex. The core HDAC complex may also associate with MTA2, MBD3, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylase complex (the NuRD complex). The NuRD complex may also interact with MBD3L1 and MBD3L2. Interacts with MTA1. Subunit of the PRC2/EED-EZH2 complex, which is composed of at least EED, EZH2, RBBP4, RBBP7 and SUZ12 (PubMed:12435631). The PRC2/EED-EZH2 complex may also associate with HDAC1. Part of the nucleosome remodeling factor (NURF) complex which consists of SMARCA1; BPTF; RBBP4 and RBBP7. Interacts with the viral protein-binding domain of the retinoblastoma protein (RB1) (PubMed:7503932, PubMed:10220405). Interacts with CREBBP, and this interaction may be enhanced by the binding of phosphorylated CREB1 to CREBBP. Interacts with BRCA1, HDAC7 and SUV39H1. Interacts with CENPA (PubMed:25556658).SIMILARITY Belongs to the WD repeat RBAP46/RBAP48/MSI1 family. UniProt Q16576 2 EQUAL 425 EQUAL Reactome Database ID Release 78 212227 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212227 Reactome R-HSA-212227 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212227.1 1 MBD3 Methyl-CpG-binding domain protein 3 MBD3_HUMAN Reactome DB_ID: 4657010 UniProt:O95983 MBD3 MBD3 FUNCTION Acts as transcriptional repressor and plays a role in gene silencing. Does not bind to DNA by itself (PubMed:12124384). Binds to DNA with a preference for sites containing methylated CpG dinucleotides (in vitro). Binds to a lesser degree DNA containing unmethylated CpG dinucleotides (PubMed:24307175). Recruits histone deacetylases and DNA methyltransferases.SUBUNIT Heterodimer with MBD2. Part of the NuRD and the MeCP1 complex. Interacts with BCL6, HDAC1, MTA2, DNMT1, p66-alpha and p66-beta. UniProt O95983 1 EQUAL 291 EQUAL Reactome Database ID Release 78 4657010 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4657010 Reactome R-HSA-4657010 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4657010.1 1 Reactome Database ID Release 78 4657018 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4657018 Reactome R-HSA-4657018 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4657018.2 ComplexPortal CPX-880 ComplexPortal CPX-922 1 Reactome Database ID Release 78 427352 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=427352 Reactome R-HSA-427352 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-427352.1 LEFT-TO-RIGHT Assembly of RNA Polymerase I Holoenzyme (human) At the beginning of this reaction, 1 molecule of each of POLR1A (RPA190, A194), POLR1B (RPA135), POLR1C (RPA40), POLR1D (RPA19), POLR1E (PAF53, RPA49), POLR2E (RPB5), POLR2F (RPB6), POLR2H (RPB8), POLR2K (RPABC4, RPB12), POLR2L (RPB10), TWISTNB (RPA43), CD3EAP (CAST, PAF49), and ZNRD1 (RPA12) are present. At the end of this reaction, 1 molecule of 'RNA Polymerase I Holoenzyme (Human)' is present.<br> This reaction takes place in the 'nucleolus'.<br> POLR1B DNA-directed RNA polymerase I 135 kDa polypeptide RNA polymerase I subunit 2 RPA135 Reactome DB_ID: 63496 UniProt:Q9H9Y6 POLR1B POLR1B FUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Second largest core component of RNA polymerase I which synthesizes ribosomal RNA precursors. Proposed to contribute to the polymerase catalytic activity and forms the polymerase active center together with the largest subunit. Pol I is composed of mobile elements and RPA2 is part of the core element with the central large cleft and probably a clamp element that moves to open and close the cleft.SUBUNIT Component of the RNA polymerase I (Pol I) complex consisting of at least 13 subunits.SIMILARITY Belongs to the RNA polymerase beta chain family. UniProt Q9H9Y6 1 EQUAL 1135 EQUAL Reactome Database ID Release 78 63496 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=63496 Reactome R-HSA-63496 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-63496.1 POLR2K DNA-directed RNA polymerases I, II, and III 7.0 kDa polypeptide ABC10-alpha RPB7.0 RPB10alpha RPABC4 Reactome DB_ID: 63537 UniProt:P53803 POLR2K POLR2K FUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I, II and III which synthesize ribosomal RNA precursors, mRNA precursors and many functional non-coding RNAs, and a small RNAs, such as 5S rRNA and tRNAs, respectively.SUBUNIT Component of the RNA polymerase I (Pol I), RNA polymerase II (Pol II) and RNA polymerase III (Pol III) complexes consisting of at least 13, 12 and 17 subunits, respectively.SIMILARITY Belongs to the archaeal RpoP/eukaryotic RPC10 RNA polymerase subunit family. UniProt P53803 1 EQUAL 58 EQUAL Reactome Database ID Release 78 63537 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=63537 Reactome R-HSA-63537 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-63537.1 RPB6 POLR2F HsRPABC2 DNA-directed RNA polymerase II 14.4 kDa polypeptide (EC 2.7.7.6) (RPB6) (RPB14.4) DNA-directed RNA polymerase II 14.4 kDa polypeptide RPB14.4 RPABC2 Reactome DB_ID: 83714 UniProt:P61218 POLR2F POLR2F POLRF FUNCTION DNA-dependent RNA polymerases catalyze the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I, II, and III which synthesize ribosomal RNA precursors, mRNA precursors and many functional non-coding RNAs, and small RNAs, such as 5S rRNA and tRNAs, respectively. Pol II is the central component of the basal RNA polymerase II transcription machinery. Pols are composed of mobile elements that move relative to each other. In Pol II, POLR2F/RPB6 is part of the clamp element and together with parts of RPB1 and RPB2 forms a pocket to which the RPB4-RPB7 subcomplex binds (By similarity).SUBUNIT Component of the RNA polymerase I (Pol I), RNA polymerase II (Pol II) and RNA polymerase III (Pol III) complexes consisting of at least 13, 12 and 17 subunits, respectively.SIMILARITY Belongs to the archaeal RpoK/eukaryotic RPB6 RNA polymerase subunit family. UniProt P61218 2 EQUAL 127 EQUAL Reactome Database ID Release 78 83714 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=83714 Reactome R-HSA-83714 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-83714.1 TWISTNB DNA-directed RNA polymerase I subunit RPA43 RPA43_HUMAN Reactome DB_ID: 5419290 UniProt:Q3B726 POLR1F POLR1F TWISTNB FUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of RNA polymerase I which synthesizes ribosomal RNA precursors. Through its association with RRN3/TIF-IA may be involved in recruitment of Pol I to rDNA promoters.SUBUNIT Component of the RNA polymerase I (Pol I) complex consisting of at least 13 subunits (By similarity). Interacts with RRN3/TIF-IA.TISSUE SPECIFICITY Widely expressed. Expressed in all fetal and adult tissues tested, with highest expression in fetal lung, liver, and kidney, and low expression in all adult tissues.SIMILARITY Belongs to the eukaryotic RPA43 RNA polymerase subunit family. UniProt Q3B726 1 EQUAL 338 EQUAL Reactome Database ID Release 78 5419290 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5419290 Reactome R-HSA-5419290 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5419290.1 ZNRD1 DNA-directed RNA polymerase I subunit RPA12 RPA12_HUMAN Reactome DB_ID: 5419292 UniProt:Q9P1U0 POLR1H POLR1H RPA12 ZNRD1 FUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of RNA polymerase I which synthesizes ribosomal RNA precursors.SUBUNIT Component of the RNA polymerase I (Pol I) complex consisting of at least 13 subunits.SIMILARITY Belongs to the archaeal RpoM/eukaryotic RPA12/RPB9/RPC11 RNA polymerase family. UniProt Q9P1U0 1 EQUAL 126 EQUAL Reactome Database ID Release 78 5419292 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5419292 Reactome R-HSA-5419292 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5419292.1 POLR1E DNA-directed RNA polymerase I subunit RPA49 RPA49_HUMAN Reactome DB_ID: 5419294 UniProt:Q9GZS1 POLR1E POLR1E PAF53 PRAF1 FUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of RNA polymerase I which synthesizes ribosomal RNA precursors (PubMed:24207024). Appears to be involved in the formation of the initiation complex at the promoter by mediating the interaction between Pol I and UBTF/UBF (PubMed:24207024).SUBUNIT Component of the RNA polymerase I (Pol I) complex consisting of at least 13 subunits (PubMed:16809778, PubMed:29065309). Interacts with POLR1G (By similarity). Also binds UBTF/UBF (By similarity). Interacts with PWP1 (PubMed:29065309).PTM Acetylated at Lys-373 by CREBBP/CBP, leading to decreased RNA polymerase I transcription (PubMed:24207024). In normal conditions, deacetylated by SIRT7, promoting the association of RNA polymerase I with the rDNA promoter region and coding region (PubMed:24207024). In response to stress, SIRT7 is released from nucleoli leading to hyperacetylation of POLR1E/PAF53 and decreased association of RNA polymerase I with the rDNA promoter region (PubMed:24207024).SIMILARITY Belongs to the eukaryotic RPA49/POLR1E RNA polymerase subunit family. UniProt Q9GZS1 1 EQUAL 481 EQUAL Reactome Database ID Release 78 5419294 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5419294 Reactome R-HSA-5419294 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5419294.1 RPB10 POLR2L HsRPABC5 DNA-directed RNA polymerase II 7.6 kDa polypeptide (EC 2.7.7.6) (RPB10) (RPB7.6) DNA-directed RNA polymerase II 7.6 kDa polypeptide RPB7.6 RPABC5 Reactome DB_ID: 83715 UniProt:P62875 POLR2L POLR2L FUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I, II and III which synthesize ribosomal RNA precursors, mRNA precursors and many functional non-coding RNAs, and a small RNAs, such as 5S rRNA and tRNAs, respectively. Pol II is the central component of the basal RNA polymerase II transcription machinery. Pols are composed of mobile elements that move relative to each other. In Pol II, POLR2L/RBP10 is part of the core element with the central large cleft (By similarity).SUBUNIT Component of the RNA polymerase I (Pol I), RNA polymerase II (Pol II) and RNA polymerase III (Pol III) complexes consisting of at least 13, 12 and 17 subunits, respectively.SIMILARITY Belongs to the archaeal RpoN/eukaryotic RPB10 RNA polymerase subunit family. UniProt P62875 1 EQUAL 67 EQUAL Reactome Database ID Release 78 83715 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=83715 Reactome R-HSA-83715 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-83715.1 POLR1A DNA-directed RNA polymerase I largest subunit RNA polymerase I 194 kDa subunit RPA194 Reactome DB_ID: 63494 UniProt:O95602 POLR1A POLR1A FUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Largest and catalytic core component of RNA polymerase I which synthesizes ribosomal RNA precursors. Forms the polymerase active center together with the second largest subunit. A single stranded DNA template strand of the promoter is positioned within the central active site cleft of Pol I. A bridging helix emanates from RPA1 and crosses the cleft near the catalytic site and is thought to promote translocation of Pol I by acting as a ratchet that moves the RNA-DNA hybrid through the active site by switching from straight to bent conformations at each step of nucleotide addition (By similarity).SUBUNIT Component of the RNA polymerase I (Pol I) complex consisting of at least 13 subunits (PubMed:16809778). Interacts with MYO1C (By similarity). Interacts with ERBB2 (PubMed:21555369). Interacts with DDX11 (PubMed:26089203).SIMILARITY Belongs to the RNA polymerase beta' chain family. UniProt O95602 1 EQUAL 1720 EQUAL Reactome Database ID Release 78 63494 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=63494 Reactome R-HSA-63494 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-63494.1 RPB8 POLR2H DNA-directed RNA polymerases I, II, and III 17.1 kDa polypeptide RPB17 RPABC3 Reactome DB_ID: 63523 UniProt:P52434 POLR2H POLR2H FUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I, II and III which synthesize ribosomal RNA precursors, mRNA precursors and many functional non-coding RNAs, and small RNAs, such as 5S rRNA and tRNAs, respectively.SUBUNIT Component of the RNA polymerase I (Pol I), RNA polymerase II (Pol II) and RNA polymerase III (Pol III) complexes consisting of at least 13, 12 and 17 subunits, respectively. Directly interacts with POLR2A.SIMILARITY Belongs to the eukaryotic RPB8 RNA polymerase subunit family. UniProt P52434 2 EQUAL 150 EQUAL Reactome Database ID Release 78 63523 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=63523 Reactome R-HSA-63523 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-63523.1 CD3EAP DNA-directed RNA polymerase I subunit RPA34 RPA34_HUMAN Reactome DB_ID: 5419289 UniProt:O15446 POLR1G POLR1G ASE1 CAST CD3EAP PAF49 FUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of RNA polymerase I which synthesizes ribosomal RNA precursors. Isoform 1 is involved in UBTF-activated transcription, presumably at a step following PIC formation.FUNCTION Isoform 2 has been described as a component of preformed T-cell receptor (TCR) complex.SUBUNIT Component of the RNA polymerase I (Pol I) complex consisting of at least 13 subunits. Interacts with TAF1A thereby associates with the SL1 complex. Interacts with UBTF. Interacts with POLR1E/PRAF1 through its N-terminal region (By similarity). Isoform 2 interacts with CD3E.PTM Isoform 2 undergoes tyrosine phosphorylation upon T-cell receptor (TCR) stimulation. This phosphorylation has not been confirmed by other groups.PTM Isoform 1 is phosphorylated on tyrosine residues in initiation-competent Pol I-beta complexes but not in Pol I-alpha complexes.MISCELLANEOUS It is in an antisense orientation to and overlaps the gene of the DNA repair enzyme ERCC1. This gene overlap is conserved in mouse, suggesting an important biological function.SIMILARITY Belongs to the eukaryotic RPA34 RNA polymerase subunit family.CAUTION It is not known whether the so-called human ASE1 and human CAST proteins represent two sides of a single gene product with sharply different functional characteristics. Experiments done with the mouse homolog protein are in favor of an implication of this gene in rRNA transcription instead of T-cell receptor signaling. UniProt O15446 1 EQUAL 510 EQUAL Reactome Database ID Release 78 5419289 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5419289 Reactome R-HSA-5419289 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5419289.1 XAP4 POLR2E HsRPABC1 DNA-directed RNA polymerase II 23 kDa polypeptide (EC 2.7.7.6) (RPB25) (XAP4) (RPB5) DNA-directed RNA polymerase II 23 kDa polypeptide RPB25 RPB5 RPABC1 Reactome DB_ID: 83713 UniProt:P19388 POLR2E POLR2E FUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I, II and III which synthesize ribosomal RNA precursors, mRNA precursors and many functional non-coding RNAs, and small RNAs, such as 5S rRNA and tRNAs, respectively. Pol II is the central component of the basal RNA polymerase II transcription machinery. Pols are composed of mobile elements that move relative to each other. In Pol II, POLR2E/RPB5 is part of the lower jaw surrounding the central large cleft and thought to grab the incoming DNA template. Seems to be the major component in this process (By similarity).SUBUNIT Component of the RNA polymerase I (Pol I), RNA polymerase II (Pol II) and RNA polymerase III (Pol III) complexes consisting of at least 13, 12 and 17 subunits, respectively (By similarity). In RNA Pol II, this subunit is present in 2-fold molar excess over the other subunits. Interacts with URI1.SUBUNIT (Microbial infection) Interacts with HBV protein X.SIMILARITY Belongs to the archaeal RpoH/eukaryotic RPB5 RNA polymerase subunit family. UniProt P19388 1 EQUAL 210 EQUAL Reactome Database ID Release 78 83713 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=83713 Reactome R-HSA-83713 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-83713.1 AC19 POLR1D HsRPAC2 DNA-directed RNA polymerases I and III subunit RPAC2 RPA16 DNA-directed RNA polymerase I and III 16 kDa polypeptide Reactome DB_ID: 63500 UniProt:P0DPB5 POLR1D POLR1D CAUTION POLR1D isoform 2 lacks an RNA polymerase domain and therefore cannot have DNA-dependent RNA polymerase function. UniProt P0DPB5 1 EQUAL 133 EQUAL Reactome Database ID Release 78 63500 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=63500 Reactome R-HSA-63500 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-63500.2 RPA40 POLR1C HsRPAC1 DNA-directed RNA polymerases I and III subunit RPAC1 DNA-directed RNA polymerase I and III 40 kDa polypeptide RPA39 Reactome DB_ID: 63498 UniProt:O15160 POLR1C POLR1C POLR1E FUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I and III which synthesize ribosomal RNA precursors and small RNAs, such as 5S rRNA and tRNAs, respectively. RPAC1 is part of the Pol core element with the central large cleft and probably a clamp element that moves to open and close the cleft (By similarity).SUBUNIT Component of the RNA polymerase I (Pol I) and RNA polymerase III (Pol III) complexes consisting of at least 13 and 17 subunits, respectively.SIMILARITY Belongs to the archaeal RpoD/eukaryotic RPB3 RNA polymerase subunit family. UniProt O15160 2 EQUAL 346 EQUAL Reactome Database ID Release 78 63498 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=63498 Reactome R-HSA-63498 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-63498.1 RNA Polymerase I Holoenzyme Reactome DB_ID: 73859 1 1 1 1 1 1 1 1 1 1 1 1 1 Reactome Database ID Release 78 73859 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73859 Reactome R-HSA-73859 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73859.1 Reactome Database ID Release 78 73865 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73865 Reactome R-HSA-73865 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73865.2 LEFT-TO-RIGHT Binding of RRN3 to RNA Polymerase I After the assembly of the RNA Polymerase I Holoenzyme, Rrn3 binding occurs (Engel et al. 2016, Pilsl et al. 2016). Authored: Gillespie, ME, 2003-09-02 00:00:00 Edited: Gillespie, ME, 0000-00-00 00:00:00 RRN3 Rrn3 Reactome DB_ID: 73714 UniProt:Q9NYV6 RRN3 RRN3 TIFIA FUNCTION Required for efficient transcription initiation by RNA polymerase I. Required for the formation of the competent preinitiation complex (PIC). Dissociates from pol I as a consequence of transcription. In vitro, cannot activate transcription in a subsequent transcription reaction (By similarity).SUBUNIT Interacts with POLR1F, EIF3L, TAF1B and TAF1C.PTM Phosphorylation is required for participation in rDNA transcription (By similarity). Phosphorylated at Thr-200 by MAPK9/JNK2, which abrogates initiation complex formation.SIMILARITY Belongs to the RRN3 family. UniProt Q9NYV6 1 EQUAL 651 EQUAL Reactome Database ID Release 78 73714 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73714 Reactome R-HSA-73714 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73714.1 Active RNA Polymerase I Reactome DB_ID: 73715 1 1 Reactome Database ID Release 78 73715 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73715 Reactome R-HSA-73715 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73715.1 Reactome Database ID Release 78 73757 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73757 Reactome R-HSA-73757 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73757.3 27418309 Pubmed 2016 RNA polymerase I-Rrn3 complex at 4.8 Å resolution Engel, Christoph Plitzko, Jürgen Cramer, P Nat Commun 7:12129 27418187 Pubmed 2016 Structure of the initiation-competent RNA polymerase I and its implication for transcription Pilsl, Michael Crucifix, Corinne Papai, Gabor Krupp, Ferdinand Steinbauer, Robert Griesenbeck, Joachim Milkereit, Philipp Tschochner, Herbert Schultz, Patrick Nat Commun 7:12126 LEFT-TO-RIGHT Recruitment of Active RNA Polymerase I to SL1:phos.UBF-1:rDNA Promoter Composed of Acetylated SL1, phosphorylated UBF-1 bound the rDNA promoter as well as the active RNA polymerase holoenzyme, rrn3 and TFIIH the transcription initiation complex is complete. The assembly picture is incomplete, as the point at which TFIIH joins the complex is unknown, though by the time that this complex is formed TFIIH is present (it has been included at this step for completeness). This forms the transcriptionally active enzyme, that is capable of initiating transcription from the rDNA promoter. Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 TFIIH Reactome DB_ID: 109634 CAK Reactome DB_ID: 69221 CAK CDK7 Cdk7 Cell division protein kinase 7 (EC 2.7.1.-) (CDK-activating kinase) (CAK)(TFIIH) (basal transcription factor complex kinase subunit) (39 kDa protein kinase) (P39 Mo15)(STK1)(CAK1) Cell division protein kinase 7 CDK-activating kinase TFIIH basal transcription factor complex kinase subunit 39 kDa protein kinase P39 Mo15 STK1 CAK1 Reactome DB_ID: 69218 UniProt:P50613 CDK7 CDK7 CAK CAK1 CDKN7 MO15 STK1 FUNCTION Serine/threonine kinase involved in cell cycle control and in RNA polymerase II-mediated RNA transcription. Cyclin-dependent kinases (CDKs) are activated by the binding to a cyclin and mediate the progression through the cell cycle. Each different complex controls a specific transition between 2 subsequent phases in the cell cycle. Required for both activation and complex formation of CDK1/cyclin-B during G2-M transition, and for activation of CDK2/cyclins during G1-S transition (but not complex formation). CDK7 is the catalytic subunit of the CDK-activating kinase (CAK) complex. Phosphorylates SPT5/SUPT5H, SF1/NR5A1, POLR2A, p53/TP53, CDK1, CDK2, CDK4, CDK6 and CDK11B/CDK11. CAK activates the cyclin-associated kinases CDK1, CDK2, CDK4 and CDK6 by threonine phosphorylation, thus regulating cell cycle progression. CAK complexed to the core-TFIIH basal transcription factor activates RNA polymerase II by serine phosphorylation of the repetitive C-terminal domain (CTD) of its large subunit (POLR2A), allowing its escape from the promoter and elongation of the transcripts. Phosphorylation of POLR2A in complex with DNA promotes transcription initiation by triggering dissociation from DNA. Its expression and activity are constant throughout the cell cycle. Upon DNA damage, triggers p53/TP53 activation by phosphorylation, but is inactivated in turn by p53/TP53; this feedback loop may lead to an arrest of the cell cycle and of the transcription, helping in cell recovery, or to apoptosis. Required for DNA-bound peptides-mediated transcription and cellular growth inhibition.ACTIVITY REGULATION Inactivated by phosphorylation. Repressed by roscovitine (seliciclib, CYC202), R547 (Ro-4584820) and SNS-032 (BMS-387032). The association of p53/TP53 to the CAK complex in response to DNA damage reduces kinase activity toward CDK2 and RNA polymerase II repetitive C-terminal domain (CTD), thus stopping cell cycle progression. The inactivation by roscovitine promotes caspase-mediated apoptosis in leukemic cells.SUBUNIT Associates primarily with cyclin-H (CCNH) and MAT1 to form the CAK complex. CAK can further associate with the core-TFIIH to form the TFIIH basal transcription factor; this complex is sensitive to UV light. The CAK complex binds to p53/TP53 in response to DNA damage. Interacts with CDK2, SF1/NR5A1, PUF60 and PRKCI.TISSUE SPECIFICITY Ubiquitous.INDUCTION Repressed by DNA-bound peptides.PTM Phosphorylation of Ser-164 during mitosis inactivates the enzyme. Phosphorylation of Thr-170 is required for activity. Phosphorylated at Ser-164 and Thr-170 by CDK2.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. UniProt P50613 1 EQUAL 346 EQUAL Reactome Database ID Release 78 69218 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=69218 Reactome R-HSA-69218 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-69218.2 1 p37 CCNH Cyclin H MO15-associated protein p34 Reactome DB_ID: 69220 UniProt:P51946 CCNH CCNH FUNCTION Regulates CDK7, the catalytic subunit of the CDK-activating kinase (CAK) enzymatic complex. CAK activates the cyclin-associated kinases CDK1, CDK2, CDK4 and CDK6 by threonine phosphorylation. CAK complexed to the core-TFIIH basal transcription factor activates RNA polymerase II by serine phosphorylation of the repetitive C-terminal domain (CTD) of its large subunit (POLR2A), allowing its escape from the promoter and elongation of the transcripts. Involved in cell cycle control and in RNA transcription by RNA polymerase II. Its expression and activity are constant throughout the cell cycle.SUBUNIT Associates primarily with CDK7 and MAT1 to form the CAK complex. CAK can further associate with the core-TFIIH to form the TFIIH basal transcription factor.SIMILARITY Belongs to the cyclin family. Cyclin C subfamily. UniProt P51946 1 EQUAL 323 EQUAL Reactome Database ID Release 78 69220 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=69220 Reactome R-HSA-69220 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-69220.2 1 p36 MNAT1 MAT1 CDK-activating kinase assembly factor MAT1 (RING finger protein MAT1) (Menage a trois) (CDK7/cyclin H assembly factor) (p36) (p35) (Cyclin G1 interacting protein) CDK-activating kinase assembly factor MAT1 RING finger protein MAT1 Menage a trois CDK7/cyclin H assembly factor p35 Cyclin G1 interacting protein Reactome DB_ID: 59012 UniProt:P51948 MNAT1 MNAT1 CAP35 MAT1 RNF66 FUNCTION Stabilizes the cyclin H-CDK7 complex to form a functional CDK-activating kinase (CAK) enzymatic complex. CAK activates the cyclin-associated kinases CDK1, CDK2, CDK4 and CDK6 by threonine phosphorylation. CAK complexed to the core-TFIIH basal transcription factor activates RNA polymerase II by serine phosphorylation of the repetitive C-terminal domain (CTD) of its large subunit (POLR2A), allowing its escape from the promoter and elongation of the transcripts. Involved in cell cycle control and in RNA transcription by RNA polymerase II.SUBUNIT Associates primarily with CDK7 and cyclin H to form the CAK complex. CAK can further associate with the core-TFIIH to form the TFIIH basal transcription factor.TISSUE SPECIFICITY Highest levels in colon and testis. Moderate levels are present thymus, prostate, ovary, and small intestine. The lowest levels are found in spleen and leukocytes. UniProt P51948 1 EQUAL 309 EQUAL Reactome Database ID Release 78 59012 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=59012 Reactome R-HSA-59012 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-59012.1 1 Reactome Database ID Release 78 69221 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=69221 Reactome R-HSA-69221 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-69221.1 ComplexPortal CPX-578 1 TTDA GTF2H5 General transcription factor IIH subunit 5 TFB5 ortholog General transcription factor IIH polypeptide 5 TFIIH basal transcription factor complex TTD-A subunit Reactome DB_ID: 5688446 UniProt:Q6ZYL4 GTF2H5 GTF2H5 C6orf175 TTDA FUNCTION Component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. In transcription, TFIIH has an essential role in transcription initiation. When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription. Necessary for the stability of the TFIIH complex and for the presence of normal levels of TFIIH in the cell.SUBUNIT Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK-activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription.SIMILARITY Belongs to the TFB5 family. UniProt Q6ZYL4 1 EQUAL 71 EQUAL Reactome Database ID Release 78 5688446 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5688446 Reactome R-HSA-5688446 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5688446.1 1 ERCC3 XPB protein ERCC-3 TFIIH basal transcription factor complex helicase XPB subunit (EC 3.6.1.-) (Basic transcription factor 2 89 kDa subunit) (BTF2-p89) (TFIIH 89 kDa subunit) (DNA-repair protein complementing XP-B cells) (Xeroderma pigmentosum group B complementing protein) (DNA excision repair protein ERCC-3) TFIIH basal transcription factor complex helicase XPB subunit Basic transcription factor 2 89 kDa subunit BTF2-p89 TFIIH 89 kDa subunit DNA-repair protein complementing XP-B cells Xeroderma pigmentosum group B complementing protein DNA excision repair protein ERCC-3 Reactome DB_ID: 67439 UniProt:P19447 ERCC3 ERCC3 XPB XPBC FUNCTION ATP-dependent 3'-5' DNA helicase, component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. The ATPase activity of XPB/ERCC3, but not its helicase activity, is required for DNA opening. In transcription, TFIIH has an essential role in transcription initiation (PubMed:8157004, PubMed:30894545). When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape (PubMed:8157004). The ATP-dependent helicase activity of XPB/ERCC3 is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription.SUBUNIT Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK-activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription (PubMed:9852112). Interacts with PUF60 (PubMed:10882074, PubMed:11239393). Interacts with ATF7IP (PubMed:19106100). Interacts with KAT2A; leading to KAT2A recruitment to promoters and acetylation of histones (PubMed:30894545).SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus EBNA2.SIMILARITY Belongs to the helicase family. RAD25/XPB subfamily. UniProt P19447 1 EQUAL 782 EQUAL Reactome Database ID Release 78 67439 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=67439 Reactome R-HSA-67439 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-67439.1 1 CXPD ERCC2 XPD protein ERCC2/CXPD TFIIH basal transcription factor complex helicase subunit (EC 3.6.1.-) (DNA-repair protein complementing XP-D cells) (Xeroderma pigmentosum group D complementing protein) (CXPD) (DNA excision repair protein ERCC-2) TFIIH basal transcription factor complex helicase subunit DNA-repair protein complementing XP-D cells Xeroderma pigmentosum group D complementing protein DNA excision repair protein ERCC-2 Reactome DB_ID: 67443 UniProt:P18074 ERCC2 ERCC2 XPD XPDC FUNCTION ATP-dependent 5'-3' DNA helicase, component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. The ATP-dependent helicase activity of XPD/ERCC2 is required for DNA opening. In transcription, TFIIH has an essential role in transcription initiation. When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription. XPD/ERCC2 acts by forming a bridge between CAK and the core-TFIIH complex. Involved in the regulation of vitamin-D receptor activity. As part of the mitotic spindle-associated MMXD complex it plays a role in chromosome segregation. Might have a role in aging process and could play a causative role in the generation of skin cancers.SUBUNIT Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK-activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription. The interaction with GTF2H2 results in the stimulation of the 5'--&gt;3' helicase activity (PubMed:9771713, PubMed:9852112). Component of the MMXD complex, which includes CIAO1, ERCC2, CIAO2B, MMS19 and SLC25A5 (PubMed:20797633). Interacts with CIAO1 and CIAO2B; the interaction WITH CIAO2B is direct (PubMed:23891004). Interacts with ATF7IP (PubMed:19106100). Interacts directly with MMS19 (PubMed:23585563).SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus EBNA2.PTM ISGylated.SIMILARITY Belongs to the helicase family. RAD3/XPD subfamily. UniProt P18074 1 EQUAL 760 EQUAL Reactome Database ID Release 78 67443 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=67443 Reactome R-HSA-67443 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-67443.1 1 GTF2H1 TFIIH basal transcription factor complex p62 subunit Basic transcription factor 62 kDa subunit BTF2-p62 General transcription factor IIH polypeptide 1 Reactome DB_ID: 65912 UniProt:P32780 GTF2H1 GTF2H1 BTF2 FUNCTION Component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. In transcription, TFIIH has an essential role in transcription initiation. When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription.SUBUNIT Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK-activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription. Interacts with PUF60.SIMILARITY Belongs to the TFB1 family. UniProt P32780 1 EQUAL 548 EQUAL Reactome Database ID Release 78 65912 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=65912 Reactome R-HSA-65912 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-65912.1 1 GTF2H4 BTF2-p52 (TFIIH component) TFIIH basal transcription factor complex p52 subunit (Basic transcription factor 52 kDa subunit) (BTF2-p52) (General transcription factor IIH polypeptide 4) TFIIH basal transcription factor complex p52 subunit Basic transcription factor 52 kDa subunit BTF2-p52 General transcription factor IIH polypeptide 4 Reactome DB_ID: 65918 UniProt:Q92759 GTF2H4 GTF2H4 FUNCTION Component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. In transcription, TFIIH has an essential role in transcription initiation. When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription.SUBUNIT Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK-activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription.SIMILARITY Belongs to the TFB2 family. UniProt Q92759 1 EQUAL 462 EQUAL Reactome Database ID Release 78 65918 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=65918 Reactome R-HSA-65918 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-65918.1 1 GTF2H2 BTF2-p44 (TFIIH component) TFIIH basal transcription factor complex p44 subunit (Basic transcription factor 2 44 kDa subunit) (BTF2-p44) (General transcription factor IIH polypeptide 2) TFIIH basal transcription factor complex p44 subunit Basic transcription factor 2 44 kDa subunit BTF2-p44 General transcription factor IIH polypeptide 2 Reactome DB_ID: 65914 UniProt:Q13888 GTF2H2 GTF2H2 BTF2P44 FUNCTION Component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. In transcription, TFIIH has an essential role in transcription initiation. When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription. The N-terminus of GTF2H2 interacts with and regulates XPD whereas an intact C-terminus is required for a successful escape of RNAP II form the promoter.SUBUNIT Component of the TFIID-containing RNA polymerase II pre-initiation complex that is composed of TBP and at least GTF2A1, GTF2A2, GTF2E1, GTF2E2, GTF2F1, GTF2H2, GTF2H3, GTF2H4, GTF2H5, GTF2B, TCEA1, ERCC2 and ERCC3 (PubMed:27193682). Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK-activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription (PubMed:9852112, PubMed:11319235). Interacts with XPB, XPD, GTF2H1 and GTF2H3 (PubMed:11319235).SUBUNIT (Microbial infection) Interacts with varicella-zoster virus IE63 protein.TISSUE SPECIFICITY Widely expressed, with higher expression in skeletal muscle.SIMILARITY Belongs to the GTF2H2 family. UniProt Q13888 1 EQUAL 395 EQUAL Reactome Database ID Release 78 65914 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=65914 Reactome R-HSA-65914 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-65914.1 1 GTF2H3 BTF2-p34 (TFIIH component) TFIIH basal transcription factor complex p34 subunit (Basic transcription factor 2 34 kDa subunit) (BTF2-p34) (General transcription factor IIH polypeptide 3) TFIIH basal transcription factor complex p34 subunit Basic transcription factor 2 34 kDa subunit BTF2-p34 General transcription factor IIH polypeptide 3 Reactome DB_ID: 65916 UniProt:Q13889 GTF2H3 GTF2H3 FUNCTION Component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. In transcription, TFIIH has an essential role in transcription initiation. When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription.SUBUNIT Part of a TFIID-containing RNA polymerase II pre-initiation complex that is composed of TBP and at least GTF2A1, GTF2A2, GTF2E1, GTF2E2, GTF2F1, GTF2H2, GTF2H3, GTF2H4, GTF2H5, GTF2B, TCEA1, ERCC2, ERCC3, TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:27193682). Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK-activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription (PubMed:9852112). Interacts with RARA; the interaction requires prior phosphorylation of RARA on 'Ser-369' which then enhances interaction of RARA with CDK7 (By similarity).SIMILARITY Belongs to the TFB4 family. UniProt Q13889 1 EQUAL 308 EQUAL Reactome Database ID Release 78 65916 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=65916 Reactome R-HSA-65916 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-65916.1 1 Reactome Database ID Release 78 109634 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=109634 Reactome R-HSA-109634 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-109634.1 RNA Polymerase I Transcription Initiation complex Reactome DB_ID: 73716 1 1 1 Reactome Database ID Release 78 73716 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73716 Reactome R-HSA-73716 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73716.1 Reactome Database ID Release 78 73758 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73758 Reactome R-HSA-73758 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73758.2 12393749 Pubmed 2002 Multiple interactions between RNA polymerase I, TIF-IA and TAF(I) subunits regulate preinitiation complex assembly at the ribosomal gene promoter. Yuan, X Zhao, J Zentgraf, H Hoffmann-Rohrer, U Grummt, I EMBO Rep 3:1082-7 Reactome Database ID Release 78 73762 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73762 Reactome R-HSA-73762 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73762.3 RNA Polymerase I Promoter Escape As the active RNA Polymerase I complex leaves the promoter Rrn3 dissociates from the complex. RNA polymerase I Promoter Clearance is complete and Chain Elongation begins (Milkereit and Tschochner, 1998). The assembly of the initiation complex on the promoter and the transition from a closed to an open complex is then followed by promoter clearance and transcription elongation by RNA Pol I. Unlike the RNA polymerase II system, RNA polymerase I transcription does not require a form of energy such as ATP for initiation and elongation. Regulatory mechanisms operating at both the level of transcription initiation and elongation probably concurrently to adjust the level of rRNA synthesis to the need of the cell. Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 LEFT-TO-RIGHT Loss of Rrn3 from RNA Polymerase I promoter escape complex Upon transcription initiation it is thought that RRN3 is inactivated and dissociates from the Loss of Rrn3 from the RNA Polymerase I promoter escape complex. SL1 and UBF are thought to remain bound to the promoter for multiple rounds of transcription initiation Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 RNA Polymerase I promoter escape complex Reactome DB_ID: 73717 1 1 1 1 Reactome Database ID Release 78 73717 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73717 Reactome R-HSA-73717 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73717.1 Reactome Database ID Release 78 73769 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73769 Reactome R-HSA-73769 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73769.2 12646563 Pubmed 2003 Rrn3 becomes inactivated in the process of ribosomal DNA transcription. Hirschler-Laszkiewicz, I Cavanaugh, AH Mirza, A Lun, M Hu, Q Smink, T Rothblum, LI J Biol Chem 278:18953-9 LEFT-TO-RIGHT 2.7.7.6 Elongation of pre-rRNA transcript At the beginning of this reaction, 1 molecule of 'elongating pre-rRNA transcript', and 1 molecule of 'NTP' are present. At the end of this reaction, 1 molecule of 'elongating pre-rRNA transcript' is present.<br><br> This reaction takes place in the 'nucleolus' and is mediated by the 'DNA-directed RNA polymerase activity' of 'RNA Polymerase I promoter escape complex'.<br> elongating pre-rRNA transcript Reactome DB_ID: 74985 Reactome Database ID Release 78 74985 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74985 Reactome R-ALL-74985 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-74985.2 ChEBI 33697 Converted from EntitySet in Reactome NTP Reactome DB_ID: 30595 CTP cytidine 5'-triphosphate Cytidine triphosphate CTP(4-) Reactome DB_ID: 29470 CTP(4-) [ChEBI:37563] CTP(4-) ctp cytidine 5'-triphosphate(4-) CTP ChEBI CHEBI:37563 Reactome Database ID Release 78 29470 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29470 Reactome R-ALL-29470 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29470.3 COMPOUND C00063 GTP Guanosine 5'-triphosphate GTP)(4-) Reactome DB_ID: 113571 GTP(4-) [ChEBI:37565] GTP(4-) GTP gtp guanosine 5'-triphosphate(4-) ChEBI CHEBI:37565 Reactome Database ID Release 78 113571 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113571 Reactome R-ALL-113571 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113571.3 COMPOUND C00044 UTP uridine 5'-triphosphate Uridine triphosphate Reactome DB_ID: 113562 UTP(4-) [ChEBI:46398] UTP(4-) UTP utp uridine 5'-triphosphate(4-) URIDINE 5'-TRIPHOSPHATE ChEBI CHEBI:46398 Reactome Database ID Release 78 113562 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113562 Reactome R-ALL-113562 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113562.3 COMPOUND C00075 Reactome Database ID Release 78 30595 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=30595 Reactome R-ALL-30595 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-30595.1 COMPOUND C00699 ACTIVATION GENE ONTOLOGY GO:0003899 Reactome Database ID Release 78 164035 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164035 Reactome Database ID Release 78 74986 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74986 Reactome R-HSA-74986 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74986.5 14969726 Pubmed 2004 Mechanism of RNA polymerase I transcription Comai, Lucio Adv. Protein Chem. 67:123-55 ACTIVATION Reactome Database ID Release 78 427361 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=427361 Reactome R-HSA-427361 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-427361.1 Chromatin (H3K9me2):CBX3 Chromatin with H3K9me2: HP1gamma Reactome DB_ID: 427344 CBX3 HP1gamma Chromobox protein homolog 3 CBX3_HUMAN Reactome DB_ID: 427386 UniProt:Q13185 CBX3 CBX3 FUNCTION Seems to be involved in transcriptional silencing in heterochromatin-like complexes. Recognizes and binds histone H3 tails methylated at 'Lys-9', leading to epigenetic repression. May contribute to the association of the heterochromatin with the inner nuclear membrane through its interaction with lamin B receptor (LBR). Involved in the formation of functional kinetochore through interaction with MIS12 complex proteins. Contributes to the conversion of local chromatin to a heterochromatin-like repressive state through H3 'Lys-9' trimethylation, mediates the recruitment of the methyltransferases SUV39H1 and/or SUV39H2 by the PER complex to the E-box elements of the circadian target genes such as PER2 itself or PER1. Mediates the recruitment of NIPBL to sites of DNA damage at double-strand breaks (DSBs) (PubMed:28167679).SUBUNIT Binds directly to CHAF1A. Interacts with histone H3 methylated at 'Lys-9' (PubMed:11242053). Part of the E2F6.com-1 complex in G0 phase composed of E2F6, MGA, MAX, TFDP1, CBX3, BAT8, EUHMTASE1, RING1, RNF2, MBLR, L3MBTL2 and YAF2. Interacts with INCENP, TRIM28/TIF1B, KMT5B, KMT5C and SP100 (PubMed:10330177, PubMed:12004135, PubMed:9636146). Interacts with TIF1A (By similarity). Interacts with MIS12 and DSN1 (PubMed:15502821). Can interact directly with CBX5 via the chromoshadow domain (PubMed:9169472). Interacts with POGZ (PubMed:20850016, PubMed:20562864). Interacts with CHAMP1 (PubMed:20850016). The large PER complex involved in the histone methylation is composed of at least PER2, CBX3, TRIM28, SUV39H1 and/or SUV39H2; CBX3 mediates the formation of the complex. Interacts with INCENP (PubMed:9864353, PubMed:21346195). Interacts with NIPBL (via PxVxL motif) (PubMed:28167679). Interacts with LRIF1 (via PxVxL motif) (PubMed:23542155). Interacts with TTLL12 (PubMed:23251473). Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression (PubMed:32051553).PTM Phosphorylated by PIM1. Phosphorylated during interphase and possibly hyper-phosphorylated during mitosis.CAUTION Was previously reported to interact with ASXL1. However, this publication has been retracted. UniProt Q13185 1 EQUAL 183 EQUAL Reactome Database ID Release 78 427386 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=427386 Reactome R-HSA-427386 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-427386.1 1 Chromatin (H3K9me2) Reactome DB_ID: 3211683 DNA Deoxyribonucleic Acid Reactome DB_ID: 29428 Reactome Database ID Release 78 29428 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29428 Reactome R-ALL-29428 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29428.1 ChEBI 4705 1 1 Reactome Database ID Release 78 3211683 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3211683 Reactome R-HSA-3211683 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3211683.1 1 Reactome Database ID Release 78 427344 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=427344 Reactome R-HSA-427344 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-427344.1 Reactome Database ID Release 78 73772 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73772 Reactome R-HSA-73772 5 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73772.5 11032814 Pubmed 2000 The recruitment of RNA polymerase I on rDNA is mediated by the interaction of the A43 subunit with Rrn3 Peyroche, G Milkereit, P Bischler, N Tschochner, H Schultz, P Sentenac, A Carles, C Riva, M EMBO J. 19:5473-82 9649439 Pubmed 1998 A specialized form of RNA polymerase I, essential for initiation and growth-dependent regulation of rRNA synthesis, is disrupted during transcription Milkereit, P Tschochner, H EMBO J. 17:3692-703 Reactome Database ID Release 78 73854 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73854 Reactome R-HSA-73854 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73854.3 RNA Polymerase I Transcription Termination Termination of transcription by RNA polymerase I is a 4 step process. Initially TTF-1 binds the template rDNA. This complex pauses polymerase I allowing PTRF to interact with the quaternary complex releasing both pre-rRNA and Pol I from the template and TTF-1. Authored: Comai, L, 2003-07-03 17:28:24 Edited: Gillespie, ME, 0000-00-00 00:00:00 LEFT-TO-RIGHT TTF-I binds to the Sal Box As inferred from mouse cell models, the Transcription termination factor (TTF1, also known as TTF-1 and TTF-I) binds an 18 base pair sequence element known as the Sal Box found in multiple copies in the nontranscribed spacer downstream of the 28S rRNA coding region. This element is the termination signal for ribosomal gene transcription. Binding of TTF1 mediates the pausing of the elongating transcription complex. TTF1 has a relatively low affinity for purified DNA but binds cooperatively to chromatin. Oligomers of TTF1 interact in trans to bind adjacent intergenic regions and form loops of the rDNA. Binding of TTF1 to the Sal Box is also influenced by interaction of TTF1 with TIP5 and possibly other proteins. Authored: Comai, L, 2003-07-03 17:13:29 Reviewed: Shiao, YH, 2014-02-18 Reviewed: Iben, Sebastian, 2016-02-12 Edited: Gillespie, ME, 0000-00-00 00:00:00 Reactome Database ID Release 78 74987 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74987 Reactome R-HSA-74987 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74987.3 7597036 Pubmed 1995 Molecular coevolution of mammalian ribosomal gene terminator sequences and the transcription termination factor TTF-I. Evers, R Grummt, I Proc Natl Acad Sci U S A 92:5827-31 LEFT-TO-RIGHT Polymerase I Transcription Complex/Nascent Pre rRNA Complex pauses at the TTF-I:Sal Box The Polymerase I promoter escape complex/with the now complete nascent pre rRNA transcript pauses at the TTF-I bound Sal Box (Reiter et al.2012). Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 nascent pre-rRNA transcript Reactome DB_ID: 74978 NCBI Nucleotide:NR_046235 RNA45S5 45S pre-ribosomal RNA RNA45S5 NCBI Nucleotide NR_046235 1 EQUAL 13357 EQUAL Reactome Database ID Release 78 74978 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74978 Reactome R-HSA-74978 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74978.1 RNA Polymerase I:rRNATranscript:TTF-1:Sal Box Complex Reactome DB_ID: 74979 1 1 1 Reactome Database ID Release 78 74979 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74979 Reactome R-HSA-74979 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74979.1 Reactome Database ID Release 78 74994 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74994 Reactome R-HSA-74994 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74994.3 22805593 Pubmed 2012 The Reb1-homologue Ydr026c/Nsi1 is required for efficient RNA polymerase I termination in yeast Reiter, Alarich Hamperl, Stephan Seitz, Hannah Merkl, Philipp Perez-Fernandez, Jorge Williams, Lydia Gerber, Jochen Németh, Attila Léger, Isabelle Gadal, Olivier Milkereit, Philipp Griesenbeck, Joachim Tschochner, Herbert EMBO J. 31:3480-93 LEFT-TO-RIGHT PTRF Binds the Polymerase I Transcription Complex/Nascent Pre rRNA Complex paused at the TTF-I:Sal Box Dissociation of paused ternary complexes requires the Polymerase I-transcript release factor (PTRF) a leucine zipper protein. PTRF is capable of dissociating ternary Pol I transcription complexes, interacting with both TTF-I and Pol I to mediate the release of both Pol I and nascent transcripts from the template. Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 PTRF Leucine-zipper protein FKSG13 Reactome DB_ID: 74981 UniProt:Q6NZI2 CAVIN1 CAVIN1 PTRF FKSG13 FUNCTION Plays an important role in caveolae formation and organization. Essential for the formation of caveolae in all tissues (PubMed:18056712, PubMed:18191225, PubMed:19726876). Core component of the CAVIN complex which is essential for recruitment of the complex to the caveolae in presence of calveolin-1 (CAV1). Essential for normal oligomerization of CAV1. Promotes ribosomal transcriptional activity in response to metabolic challenges in the adipocytes and plays an important role in the formation of the ribosomal transcriptional loop. Dissociates transcription complexes paused by DNA-bound TTF1, thereby releasing both RNA polymerase I and pre-RNA from the template (By similarity) (PubMed:18056712, PubMed:18191225, PubMed:19726876). The caveolae biogenesis pathway is required for the secretion of proteins such as GASK1A (By similarity).SUBUNIT Component of the CAVIN complex composed of CAVIN1, CAVIN2, CAVIN3 and CAVIN4. Homotrimer (By similarity). Interacts with TTF1 (PubMed:9582279). Interacts with RNA polymerase I. Binds the 3' end of pre-rRNA. Interacts with transcription factor ZNF148 (By similarity). Interacts with LIPE in the adipocyte cytoplasm (PubMed:17026959). Interacts with CAV1 and CAVIN3 (By similarity). Interacts with CAVIN2 (PubMed:19525939, PubMed:24567387). Interacts with CAVIN4 and CAV3 (PubMed:24567387).DOMAIN The leucine-zipper domain 1 is essential for its localization in the caveolae.PTM Phosphorylated. Present in active and inactive forms. Changes in phosphorylation pattern may alter activity. Phosphorylation at Tyr-156 is essential for its functionin the regulation of ribosomal transcriptional activity.PTM Five truncated forms are found in the caveolae. These are thought to be the result of proteolysis and may be phosphorylation-dependent.PTM Monoubiquitinated.SIMILARITY Belongs to the CAVIN family. UniProt Q6NZI2 1 EQUAL 390 EQUAL Reactome Database ID Release 78 74981 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74981 Reactome R-HSA-74981 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74981.1 PTRF:Polymerase I/Nascent Pre rRNA Complex:TTF-I:Sal Box Reactome DB_ID: 74982 1 1 Reactome Database ID Release 78 74982 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74982 Reactome R-HSA-74982 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74982.1 Reactome Database ID Release 78 74993 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74993 Reactome R-HSA-74993 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74993.2 9582279 Pubmed 1998 Cloning and functional characterization of PTRF, a novel protein which induces dissociation of paused ternary transcription complexes. Jansa, P Mason, SW Hoffmann-Rohrer, U Grummt, I EMBO J 17:2855-64 LEFT-TO-RIGHT Dissociation of PTRF:Polymerase I/Nascent Pre rRNA Complex:TTF-I:Sal Box PTRF binds the quaternary complex and mediates the dissociation of paused complex. PTRF interacts with the RNA polymerase I largest subunit (p194), TTF-I and the U-rich 3' end of the nascent pre-rRNA. Authored: Comai, L, 2003-07-03 17:13:29 Edited: Gillespie, ME, 0000-00-00 00:00:00 Reactome Database ID Release 78 74992 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74992 Reactome R-HSA-74992 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-74992.2 Reactome Database ID Release 78 73863 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73863 Reactome R-HSA-73863 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73863.4 GENE ONTOLOGY GO:0006363 Reactome Database ID Release 78 73864 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73864 Reactome R-HSA-73864 3 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73864.3 GENE ONTOLOGY GO:0006360 RNA Polymerase II Transcription RNA polymerase II (Pol II) is the central enzyme that catalyses DNA- directed mRNA synthesis during the transcription of protein-coding genes. Pol II consists of a 10-subunit catalytic core, which alone is capable of elongating the RNA transcript, and a complex of two subunits, Rpb4/7, that is required for transcription initiation. <BR> The transcription cycle is divided in three major phases: initiation, elongation, and termination. Transcription initiation include promoter DNA binding, DNA melting, and initial synthesis of short RNA transcripts. The transition from initiation to elongation, is referred to as promoter escape and leads to a stable elongation complex that is characterized by an open DNA region or transcription bubble. The bubble contains the DNA-RNA hybrid, a heteroduplex of eight to nine base pairs. The growing 3-end of the RNA is engaged with the polymerase complex active site. Ultimately transcription terminates and Pol II dissocitates from the template. Generic Transcription Pathway <b>OVERVIEW OF TRANSCRIPTION REGULATION:</b> <br><br>Detailed studies of gene transcription regulation in a wide variety of eukaryotic systems has revealed the general principles and mechanisms by which cell- or tissue-specific regulation of differential gene transcription is mediated (reviewed in Naar, 2001. Kadonaga, 2004, Maston, 2006, Barolo, 2002; Roeder, 2005, Rosenfeld, 2006). Of the three major classes of DNA polymerase involved in eukaryotic gene transcription, Polymerase II generally regulates protein-encoding genes. Figure 1 shows a diagram of the various components involved in cell-specific regulation of Pol-II gene transcription. <br><br>Core Promoter: Pol II-regulated genes typically have a Core Promoter where Pol II and a variety of general factors bind to specific DNA motifs: <br> i: the TATA box (TATA DNA sequence), which is bound by the "TATA-binding protein" (TBP).<br> ii: the Initiator motif (INR), where Pol II and certain other core factors bind, is present in many Pol II-regulated genes.<br> iii: the Downstream Promoter Element (DPE), which is present in a subset of Pol II genes, and where additional core factors bind. <br>The core promoter binding factors are generally ubiquitously expressed, although there are exceptions to this.<br><br>Proximal Promoter: immediately upstream (5') of the core promoter, Pol II target genes often have a Proximal Promoter region that spans up to 500 base pairs (b.p.), or even to 1000 b.p.. This region contains a number of functional DNA binding sites for a specific set of transcription activator (TA) and transcription repressor (TR) proteins. These TA and TR factors are generally cell- or tissue-specific in expression, rather than ubiquitous, so that the presence of their cognate binding sites in the proximal promoter region programs cell- or tissue-specific expression of the target gene, perhaps in conjunction with TA and TR complexes bound in distal enhancer regions. <br><br>Distal Enhancer(s): many or most Pol II regulated genes in higher eukaryotes have one or more distal Enhancer regions which are essential for proper regulation of the gene, often in a cell or tissue-specific pattern. Like the proximal promoter region, each of the distal enhancer regions typically contain a cluster of binding sites for specific TA and/or TR DNA-binding factors, rather than just a single site. <br><br> Enhancers generally have three defining characteristics:<br> i: They can be located very long distances from the promoter of the target gene they regulate, sometimes as far as 100 Kb, or more.<br> ii: They can be either upstream (5') or downstream (3') of the target gene, including within introns of that gene.<br> iii: They can function in either orientation in the DNA.<br><br>Combinatorial mechanisms of transcription regulation: The specific combination of TA and TR binding sites within the proximal promoter and/or distal enhancer(s) provides a "combinatorial transcription code" that mediates cell- or tissue-specific expression of the associated target gene. Each promoter or enhancer region mediates expression in a specific subset of the overall expression pattern. In at least some cases, each enhancer region functions completely independently of the others, so that the overall expression pattern is a linear combination of the expression patterns of each of the enhancer modules.<br><br>Co-Activator and Co-Repressor Complexes: DNA-bound TA and TR proteins typically recruit the assembly of specific Co-Activator (Co-A) and Co-Repressor (Co-R) Complexes, respectively, which are essential for regulating target gene transcription. Both Co-A's and Co-R's are multi-protein complexes that contain several specific protein components.<br><br>Co-Activator complexes generally contain at lease one component protein that has Histone Acetyl Transferase (HAT) enzymatic activity. This functions to acetylate Histones and/or other chromatin-associated factors, which typically increases that transcription activation of the target gene. By contrast, Co-Repressor complexes generally contain at lease one component protein that has Histone De-Acetylase (HDAC) enzymatic activity. This functions to de-acetylate Histones and/or other chromatin-associated factors. This typically increases the transcription repression of the target gene.<br><br>Adaptor (Mediator) complexes: In addition to the co-activator complexes that assemble on particular cell-specific TA factors, - there are at least two additional transcriptional co-activator complexes common to most cells. One of these is the Mediator complex, which functions as an "adaptor" complex that bridges between the tissue-specific co-activator complexes assembled in the proximal promoter (or distal enhancers). The human Mediator complex has been shown to contain at least 19 protein distinct components. Different combinations of these co-activator proteins are also found to be components of specific transcription Co-Activator complexes, such as the DRIP, TRAP and ARC complexes described below. <br><br>TBP/TAF complex: Another large Co-A complex is the "TBP-associated factors" (TAFs) that assemble on TBP (TATA-Binding Protein), which is bound to the TATA box present in many promoters. There are at least 23 human TAF proteins that have been identified. Many of these are ubiquitously expressed, but TAFs can also be expressed in a cell or tissue-specific pattern. <br><br> <b> Specific Coactivator Complexes for DNA-binding Transcription Factors.</b> <br><br>A number of specific co-activator complexes for DNA-binding transcription factors have been identified, including DRIP, TRAP, and ARC (reviewed in Bourbon, 2004, Blazek, 2005, Conaway, 2005, and Malik, 2005). The DRIP co-activator complex was originally identified and named as a specific complex associated with the Vitamin D Receptor member of the nuclear receptor family of transcription factors (Rachez, 1998). Similarly, the TRAP co-activator complex was originally identified as a complex that associates with the thyroid receptor (Yuan, 1998). It was later determined that all of the components of the DRIP complex are also present in the TRAP complex, and the ARC complex (discussed further below). For example, the DRIP205 and TRAP220 proteins were show to be identical, as were specific pairs of the other components of these complexes (Rachez, 1999).<br><br>In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator ("adaptor") complex proteins (reviewed in Bourbon, 2004). The Mediator proteins were originally identified in yeast by Kornberg and colleagues, as complexes associated with DNA polymerase (Kelleher, 1990). In higher organisms, Adapter complexes bridge between the basal transcription factors (including Pol II) and tissue-specific transcription factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (Figure 1). However, many of the Mediator homologues can also be found in complexes associated with specific transcription factors in higher organisms. A unified nomenclature system for these adapter / co-activator proteins now labels them Mediator 1 through Mediator 31 (Bourbon, 2004). For example, the DRIP205 / TRAP220 proteins are now identified as Mediator 1 (Rachez, 1999), based on homology with yeast Mediator 1.<br><br> <b>Example Pathway: Specific Regulation of Target Genes During Notch Signaling:</b> <br><br>One well-studied example of cell-specific regulation of gene transcription is selective regulation of target genes during Notch signaling. Notch signaling was first identified in Drosophila, where it has been studied in detail at the genetic, molecular, biochemical and cellular levels (reviewed in Justice, 2002; Bray, 2006; Schweisguth, 2004; Louvri, 2006). In Drosophila, Notch signaling to the nucleus is thought always to be mediated by one specific DNA binding transcription factor, Suppressor of Hairless. In mammals, the homologous genes are called CBF1 (or RBPJkappa), while in worms they are called Lag-1, so that the acronym "CSL" has been given to this conserved transcription factor family. There are at least two human CSL homologues, which are now named RBPJ and RBPJL. <br><br>In Drosophila, Su(H) is known to be bifunctional, in that it represses target gene transcription in the absence of Notch signaling, but activates target genes during Notch signaling. At least some of the mammalian CSL homologues are believed also to be bifunctional, and to mediate target gene repression in the absence of Notch signaling, and activation in the presence of Notch signaling.<br><br>Notch Co-Activator and Co-Repressor complexes: This repression is mediated by at least one specific co-repressor complexes (Co-R) bound to CSL in the absence of Notch signaling. In Drosophila, this co-repressor complex consists of at least three distinct co-repressor proteins: Hairless, Groucho, and dCtBP (Drosophila C-terminal Binding Protein). Hairless has been show to bind directly to Su(H), and Groucho and dCtBP have been shown to bind directly to Hairless (Barolo, 2002). All three of the co-repressor proteins have been shown to be necessary for proper gene regulation during Notch signaling in vivo (Nagel, 2005).<br><br>In mammals, the same general pathway and mechanisms are observed, where CSL proteins are bifunctional DNA binding transcription factors (TFs), that bind to Co-Repressor complexes to mediate repression in the absence of Notch signaling, and bind to Co-Activator complexes to mediate activation in the presence of Notch signaling. However, in mammals, there may be multiple co-repressor complexes, rather than the single Hairless co-repressor complex that has been observed in Drosophila. <br><br>During Notch signaling in all systems, the Notch transmembrane receptor is cleaved and the Notch intracellular domain (NICD) translocates to the nucleus, where it there functions as a specific transcription co-activator for CSL proteins. In the nucleus, NICD replaces the Co-R complex bound to CSL, thus resulting in de-repression of Notch target genes in the nucleus (Figure 2). Once bound to CSL, NICD and CSL proteins recruit an additional co-activator protein, Mastermind, to form a CSL-NICD-Mam ternary co-activator (Co-A) complex. This Co-R complex was initially thought to be sufficient to mediate activation of at least some Notch target genes. However, there now is evidence that still other co-activators and additional DNA-binding transcription factors are required in at least some contexts (reviewed in Barolo, 2002). <br><br>Thus, CSL is a good example of a bifunctional DNA-binding transcription factor that mediates repression of specific targets genes in one context, but activation of the same targets in another context. This bifunctionality is mediated by the association of specific Co-Repressor complexes vs. specific Co-Activator complexes in different contexts, namely in the absence or presence of Notch signaling. Reviewed: Freedman, LP, 2008-02-25 20:35:15 LEFT-TO-RIGHT Formation of ARC coactivator complex ARC co-activator complex and assembly<br><br>The ARC co-activator complex is a subset of 18 proteins from the set of at least 31 Mediator proteins that, in different combinations, form "Adapter" complexes in human cells. Adapter complexes bridge between the basal transcription factors (including Pol II) and tissue-specific transcription factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (reviewed in Maston, 2006 and Naar, 2001).<br><br>The ARC complex was originally identified and named as a co-activator complex associated with transcription activator proteins (reviewed in Malik, 2005 and references therein). It was subsequently determined that many of the components of the ARC complex are also in the DRIP complex, and in the TRAP complex..<br><br>The ARC complex contains the following 14 proteins, which also are common to the DRIP and TRAP complexes: MED1, MED4, MED6, MED7, MED10, MED12, MED13, MED14, MED16, MED17, MED23, MED24, CDK8, CycC. <br><br>The ARC complex also contains 4 additional, ARC-specific components, which are now called: MED8, MED15, MED25, and MED 26 in the unified nomenclature scheme (Bourbon, 2004).<br><br>In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator complex proteins in yeast, first identified by Kornberg and colleagues (Kelleher, 1990). The unified nomenclature system for these adapter / co-activator proteins now labels them Mediator 1 through Mediator 31 (Bourbon, 2004).<br><br>The order of addition of the ARC proteins during complex assembly is not fully determined, and may vary in different cell contexts. Therefore, ARC complex assembly is represented as a single reaction event, in which all 19 components assemble simultaneously into the ARC co-activator complex.<br><br> Reviewed: Freedman, LP, 2008-02-25 20:35:15 MED16 Mediator of RNA polymerase II transcription subunit 16 MED16_HUMAN Reactome DB_ID: 556802 UniProt:Q9Y2X0 MED16 MED16 DRIP92 THRAP5 FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.SIMILARITY Belongs to the Mediator complex subunit 16 family.CAUTION It is uncertain whether Met-1 or Met-13 is the initiator. UniProt Q9Y2X0 1 EQUAL 877 EQUAL Reactome Database ID Release 78 556802 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=556802 Reactome R-HSA-556802 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-556802.1 MED1 Reactome DB_ID: 212445 UniProt:Q15648 MED1 MED1 ARC205 CRSP1 CRSP200 DRIP205 DRIP230 PBP PPARBP PPARGBP RB18A TRAP220 TRIP2 FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors (PubMed:10406464, PubMed:11867769, PubMed:12037571, PubMed:12218053, PubMed:12556447, PubMed:14636573, PubMed:15340084, PubMed:15471764, PubMed:15989967, PubMed:16574658, PubMed:9653119). Acts as a coactivator for GATA1-mediated transcriptional activation during erythroid differentiation of K562 erythroleukemia cells (PubMed:24245781).SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. This subunit specifically interacts with a number of nuclear receptors in a ligand-dependent fashion including AR, ESR1, ESR2, PPARA, PPARG, RORA, RXRA, RXRG, THRA, THRB and VDR. Interacts with CTNNB1, GABPA, GLI3, PPARGC1A and TP53. Interacts with YWHAH. Interacts with CLOCK; this interaction requires the presence of THRAP3 (By similarity). Interacts with GATA1 and CCAR1. Interacts with NR4A3 (By similarity). Interacts (via IBM motif) with PSIP1 (via IBD domain); phosphorylation increases its affinity for PSIP1 (PubMed:29997176).TISSUE SPECIFICITY Ubiquitously expressed.PTM Phosphorylated by MAPK1 or MAPK3 during G2/M phase which may enhance protein stability and promote entry into the nucleolus (PubMed:16314496). Phosphorylation increases its interaction with PSIP1 (PubMed:29997176).SIMILARITY Belongs to the Mediator complex subunit 1 family. UniProt Q15648 1 EQUAL 1581 EQUAL Reactome Database ID Release 78 212445 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212445 Reactome R-HSA-212445 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212445.1 MED8 Mediator of RNA polymerase II transcription subunit 8 MED8_HUMAN Reactome DB_ID: 556784 UniProt:Q96G25 MED8 MED8 FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. May play a role as a target recruitment subunit in E3 ubiquitin-protein ligase complexes and thus in ubiquitination and subsequent proteasomal degradation of target proteins.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. May be part of a multisubunit E3 ubiquitin-protein ligase complex with the elongin BC complex (ELOB and ELOC), CUL2 and RBX1.DOMAIN The elongin BC complex binding domain is also known as BC-box with the consensus [APST]-L-x(3)-C-x(3)-[AILV].SIMILARITY Belongs to the Mediator complex subunit 8 family. UniProt Q96G25 1 EQUAL 268 EQUAL Reactome Database ID Release 78 556784 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=556784 Reactome R-HSA-556784 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-556784.1 MED14 Reactome DB_ID: 212441 UniProt:O60244 MED14 MED14 ARC150 CRSP2 CXorf4 DRIP150 EXLM1 RGR1 TRAP170 FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Interacts with GATA1 (By similarity). Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with AR, ESR1, SREBF1 and STAT2.TISSUE SPECIFICITY Ubiquitous.SIMILARITY Belongs to the Mediator complex subunit 14 family. UniProt O60244 1 EQUAL 1454 EQUAL Reactome Database ID Release 78 212441 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212441 Reactome R-HSA-212441 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212441.1 MED10 Reactome DB_ID: 212410 UniProt:Q9BTT4 MED10 MED10 L6 TRG17 TRG20 FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.SIMILARITY Belongs to the Mediator complex subunit 10 family. UniProt Q9BTT4 1 EQUAL 135 EQUAL Reactome Database ID Release 78 212410 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212410 Reactome R-HSA-212410 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212410.1 MED7 Reactome DB_ID: 212430 UniProt:O43513 MED7 MED7 ARC34 CRSP9 FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.PTM Constitutively sumoylated.SIMILARITY Belongs to the Mediator complex subunit 7 family. UniProt O43513 1 EQUAL 233 EQUAL Reactome Database ID Release 78 212430 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212430 Reactome R-HSA-212430 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212430.1 MED17 Reactome DB_ID: 212401 UniProt:Q9NVC6 MED17 MED17 ARC77 CRSP6 DRIP77 DRIP80 TRAP80 FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Interacts with GATA1 and PPARG (By similarity). Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with STAT2.TISSUE SPECIFICITY Ubiquitous.SIMILARITY Belongs to the Mediator complex subunit 17 family. UniProt Q9NVC6 1 EQUAL 651 EQUAL Reactome Database ID Release 78 212401 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212401 Reactome R-HSA-212401 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212401.1 MED13 Reactome DB_ID: 212391 UniProt:Q9UHV7 MED13 MED13 ARC250 KIAA0593 THRAP1 TRAP240 FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.TISSUE SPECIFICITY Ubiquitous.SIMILARITY Belongs to the Mediator complex subunit 13 family. UniProt Q9UHV7 1 EQUAL 2174 EQUAL Reactome Database ID Release 78 212391 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212391 Reactome R-HSA-212391 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212391.1 MED12 Reactome DB_ID: 212343 UniProt:Q93074 MED12 MED12 ARC240 CAGH45 HOPA KIAA0192 TNRC11 TRAP230 FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. This subunit may specifically regulate transcription of targets of the Wnt signaling pathway and SHH signaling pathway.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Also interacts with CTNNB1 and GLI3.TISSUE SPECIFICITY Ubiquitous.SIMILARITY Belongs to the Mediator complex subunit 12 family. UniProt Q93074 1 EQUAL 2177 EQUAL Reactome Database ID Release 78 212343 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212343 Reactome R-HSA-212343 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212343.1 MED25 Reactome DB_ID: 212414 UniProt:Q71SY5 MED25 MED25 ACID1 ARC92 PTOV2 TCBAP0758 FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Required for RARA/RXRA-mediated transcription.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with CREBBP. Interacts with ESR1, GR, RARA, RXRA and THRB in a ligand-dependent fashion. Binds the Herpes simplex virus activator VP16.TISSUE SPECIFICITY Ubiquitously expressed. Highest levels in brain, heart, kidney, peripheral leukocytes, placenta, skeletal muscle and spleen.SIMILARITY Belongs to the Mediator complex subunit 25 family. UniProt Q71SY5 1 EQUAL 747 EQUAL Reactome Database ID Release 78 212414 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212414 Reactome R-HSA-212414 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212414.1 MED15 Mediator of RNA polymerase II transcription subunit 15 MED15_HUMAN Reactome DB_ID: 556827 UniProt:Q96RN5 MED15 MED15 ARC105 CTG7A PCQAP TIG1 TNRC7 FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Required for cholesterol-dependent gene regulation. Positively regulates the Nodal signaling pathway.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with SMAD2, SMAD3, SREBF1 and SREBF2. Interacts with WWTR1. Interacts with TRIM11.TISSUE SPECIFICITY Expressed in all tissues examined, including heart, brain, lung, spleen, thymus, pancreas, blood leukocyte and placenta. However, the level of expression varied, with highest expression in the placenta and peripheral blood and lowest in the pancreas and kidney.INDUCTION By 12-O-tetradecanoylphorbol-13-acetate (TPA).PTM Ubiquitinated by TRIM11, leading to proteasomal degradation.POLYMORPHISM The poly-Gln region from amino acids 235-262 of PCQAP is polymorphic. There are from 15 to 18 repeats in the Italian population.SIMILARITY Belongs to the Mediator complex subunit 15 family. UniProt Q96RN5 1 EQUAL 788 EQUAL Reactome Database ID Release 78 556827 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=556827 Reactome R-HSA-556827 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-556827.1 MED4 MED4_HUMAN Reactome DB_ID: 350263 UniProt:Q9NPJ6 MED4 MED4 ARC36 DRIP36 VDRIP HSPC126 FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.SIMILARITY Belongs to the Mediator complex subunit 4 family. UniProt Q9NPJ6 1 EQUAL 270 EQUAL Reactome Database ID Release 78 350263 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=350263 Reactome R-HSA-350263 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-350263.1 CDK8 Reactome DB_ID: 212440 UniProt:P49336 CDK8 CDK8 FUNCTION Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional pre-initiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. The cylin/CDK pair formed by CCNC/CDK8 also associates with the large subunit of RNA polymerase II. Interacts with CTNNB1, GLI3 and MAML1.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. UniProt P49336 1 EQUAL 464 EQUAL Reactome Database ID Release 78 212440 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212440 Reactome R-HSA-212440 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212440.1 MED23 Mediator of RNA polymerase II transcription subunit 23 MED23_HUMAN Reactome DB_ID: 556823 UniProt:Q9ULK4 MED23 MED23 ARC130 CRSP3 DRIP130 KIAA1216 SUR2 FUNCTION Required for transcriptional activation subsequent to the assembly of the pre-initiation complex (By similarity). Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional pre-initiation complex with RNA polymerase II and the general transcription factors. Required for transcriptional activation by adenovirus E1A protein. Required for ELK1-dependent transcriptional activation in response to activated Ras signaling.SUBUNIT Interacts with ELK1 (By similarity). Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with CEBPB (when not methylated), CTNNB1, and GLI3. Interacts with the adenovirus E1A protein.SIMILARITY Belongs to the Mediator complex subunit 23 family. UniProt Q9ULK4 1 EQUAL 1368 EQUAL Reactome Database ID Release 78 556823 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=556823 Reactome R-HSA-556823 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-556823.1 CCNC CycC Reactome DB_ID: 212418 UniProt:P24863 CCNC CCNC FUNCTION Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Binds to and activates cyclin-dependent kinase CDK8 that phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. The cylin/CDK pair formed by CCNC/CDK8 also associates with the large subunit of RNA polymerase II.TISSUE SPECIFICITY Highest levels in pancreas. High levels in heart, liver, skeletal muscle and kidney. Low levels in brain.SIMILARITY Belongs to the cyclin family. Cyclin C subfamily. UniProt P24863 1 EQUAL 283 EQUAL Reactome Database ID Release 78 212418 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212418 Reactome R-HSA-212418 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212418.1 MED6 Reactome DB_ID: 212359 UniProt:O75586 MED6 MED6 ARC33 FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with CTNNB1 and GLI3.SIMILARITY Belongs to the Mediator complex subunit 6 family. UniProt O75586 1 EQUAL 246 EQUAL Reactome Database ID Release 78 212359 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212359 Reactome R-HSA-212359 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212359.1 MED24 Reactome DB_ID: 212331 UniProt:O75448 MED24 MED24 ARC100 CRSP4 DRIP100 KIAA0130 THRAP4 TRAP100 FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with AR.TISSUE SPECIFICITY Ubiquitous. Abundant in skeletal muscle, heart and placenta.SIMILARITY Belongs to the Mediator complex subunit 24 family. UniProt O75448 1 EQUAL 989 EQUAL Reactome Database ID Release 78 212331 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212331 Reactome R-HSA-212331 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212331.1 MED26 Mediator of RNA polymerase II transcription subunit 26 MED26_HUMAN Reactome DB_ID: 556783 UniProt:O95402 MED26 MED26 ARC70 CRSP7 FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional pre-initiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. Interacts with CEBPB (when not methylated)(PubMed:20111005).SIMILARITY Belongs to the Mediator complex subunit 26 family. UniProt O95402 1 EQUAL 600 EQUAL Reactome Database ID Release 78 556783 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=556783 Reactome R-HSA-556783 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-556783.1 ARC coactivator complex Reactome DB_ID: 212374 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Reactome Database ID Release 78 212374 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212374 Reactome R-HSA-212374 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212374.2 Reactome Database ID Release 78 212352 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212352 Reactome R-HSA-212352 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212352.2 15175151 Pubmed 2004 A unified nomenclature for protein subunits of mediator complexes linking transcriptional regulators to RNA polymerase II Bourbon, HM Aguilera, Andrés Ansari, AZ Asturias, FJ Berk, AJ Bjorklund, S Blackwell, TK Borggrefe, T Carey, M Carlson, M Conaway, Joan W Conaway, Ron C Emmons, SW Fondell, JD Freedman, LP Fukasawa, T Gustafsson, CM Han, M He, X Herman, PK Hinnebusch, Alan G Holmberg, S Holstege, FC Jaehning, JA Kim, YJ Kuras, L Leutz, A Lis, JT Meisterernest, M Naar, AM Nasmyth, K Parvin, JD Ptashne, M Reinberg, Danny Ronne, H Sadowski, I Sakurai, H Sipiczki, M Sternberg, PW Stillman, DJ Strich, R Struhl, K Svejstrup, JQ Tuck, S Winston, F Roeder, RG Kornberg, RD Mol Cell 14:553-7 9637681 Pubmed 1998 A novel protein complex that interacts with the vitamin D3 receptor in a ligand-dependent manner and enhances VDR transactivation in a cell-free system Rachez, C Suldan, Z Ward, J Chang, CP Burakov, D Erdjument-Bromage, H Tempst, P Freedman, LP Genes Dev 12:1787-800 9653119 Pubmed 1998 The TRAP220 component of a thyroid hormone receptor- associated protein (TRAP) coactivator complex interacts directly with nuclear receptors in a ligand-dependent fashion Yuan, CX Ito, M Fondell, JD Fu, ZY Roeder, RG Proc Natl Acad Sci U S A 95:7939-44 2163759 Pubmed 1990 A novel mediator between activator proteins and the RNA polymerase II transcription apparatus Kelleher RJ, 3rd Flanagan, PM Kornberg, RD Cell 61:1209-15 15896744 Pubmed 2005 Dynamic regulation of pol II transcription by the mammalian Mediator complex Malik, S Roeder, RG Trends Biochem Sci 30:256-63 10235266 Pubmed 1999 Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex Rachez, C Lemon, BD Suldan, Z Bromleigh, V Gamble, M Näär, AM Erdjument-Bromage, H Tempst, P Freedman, LP Nature 398:824-8 16719718 Pubmed 2006 Transcriptional regulatory elements in the human genome Maston, GA Evans, SK Green, MR Annu Rev Genomics Hum Genet 7:29-59 LEFT-TO-RIGHT Formation of DRIP coactivator complex DRIP co-activator complex and assembly<br><br>The DRIP co-activator complex is a subset of 14 proteins from the set of at least 31 Mediator proteins that, in different combinations, form "Adapter" complexes. Adapter complexes bridge between the basal transcription factors (including Pol II) and tissue-specific transcription factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (reviewed in Maston, 2006 and Naar, 2001).<br><br>The DRIP complex was originally identified and named as a co-activator complex associated with the Vitamin D Receptor member of the nuclear receptor family of transcription factors (Rachez, 1998). It was later determined that all of the components of the DRIP complex were also in the TRAP complex, and the ARC complex.<br><br>The DRIP complex contains the following 14 proteins, which also are common to the ARC and TRAP complexes: MED1, MED4, MED6, MED7, MED10, MED12, MED13, MED14, MED16, MED17, MED23, MED24, CDK8, CycC. <br><br>All of the DRIP adapter complex components are present in the ARC adapter complex, but the ARC complex also has 4 additional components (Rachez, 1999). These ARC-specific components are now called: MED8, MED15, MED25, and MED 26 in the unified nomenclature scheme (Bourbon, 2004).<br><br>Similarly, all 14 of the DRIP adapter complex components are present in the TRAP adapter complex, but the TRAP complex also has 4 additional components (Bourbon, 2004), These TRAP-specific components are now called: MED20, MED27, MED30, and MED 31 in the unified nomenclature scheme.<br><br>In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator complex identified in yeast, first identified by Kornberg and colleagues (Kelleher, 1990).<br><br> Reviewed: Freedman, LP, 2008-02-25 20:35:15 DRIP coactivator complex Reactome DB_ID: 212340 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Reactome Database ID Release 78 212340 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212340 Reactome R-HSA-212340 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212340.1 Reactome Database ID Release 78 212432 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212432 Reactome R-HSA-212432 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212432.2 11395415 Pubmed 2001 Transcriptional coactivator complexes Näär, AM Lemon, BD Tjian, R Annu Rev Biochem 70:475-501 LEFT-TO-RIGHT Formation of TRAP coactivator complex TRAP co-activator complex and assembly<br><br>The TRAP co-activator complex is a subset of 18 proteins from the set of at least 31 Mediator proteins that, in different combinations and in different contexts, form specific co-activator or "Adapter" complexes in human cells. These complexes bridge between the basal transcription factors (including Pol II) and tissue-specific transcription factors (TFs) bound to sites within upstream Proximal Promoter regions or distal Enhancer regions (reviewed in Maston, 2006 and Naar, 2001).<br><br>The TRAP complex was originally identified and named as a co-activator complex associated with the Thyroid Hormone Receptor member of the nuclear receptor family of transcription factors (Yuan, 1998). It was later determined that many of the components of the TRAP complex are also in the DRIP complex, and in the ARC complex.<br><br>The TRAP complex contains the following 14 proteins, which also are common to the DRIP and ARC complexes: MED1, MED4, MED6, MED7, MED10, MED12, MED13, MED14, MED16, MED17, MED23, MED24, CDK8, CycC.<br><br>The TRAP complex also contains 4 additional components, which are now called: MED20, MED27, MED30, and MED 31 in the unified nomenclature scheme (Bourbon, 2004).<br><br>In addition, these various transcription co-activator proteins identified in mammalian cells were found to be the orthologues or homologues of the Mediator complex proteins in yeast, first identified by Kornberg and colleagues (Kelleher, 1990). The unified nomenclature system for these adapter / co-activator proteins now labels them Mediator 1 through Mediator 31 (Bourbon, 2004).<br><br>The order of addition of the TRAP proteins during complex assembly is not fully determined, and may vary in different cell contexts. Therefore, TRAP co-activator complex assembly is represented as a single reaction event, in which all 18 components assemble simultaneously into the TRAP co-activator complex.<br><br> Reviewed: Freedman, LP, 2008-02-25 20:35:15 MED27 Mediator of RNA polymerase II transcription subunit 27 MED27_HUMAN Reactome DB_ID: 556761 UniProt:Q6P2C8 MED27 MED27 CRSP34 CRSP8 FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.SIMILARITY Belongs to the Mediator complex subunit 27 family. UniProt Q6P2C8 1 EQUAL 311 EQUAL Reactome Database ID Release 78 556761 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=556761 Reactome R-HSA-556761 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-556761.1 MED20 Reactome DB_ID: 212428 UniProt:Q9H944 MED20 MED20 TRFP FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Interacts with PPARG (By similarity). Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.SIMILARITY Belongs to the Mediator complex subunit 20 family. UniProt Q9H944 1 EQUAL 212 EQUAL Reactome Database ID Release 78 212428 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212428 Reactome R-HSA-212428 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212428.1 MED30 Reactome DB_ID: 212398 UniProt:Q96HR3 MED30 MED30 THRAP6 TRAP25 FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.TISSUE SPECIFICITY Expressed in brain, heart, kidney, liver, lung, pancreas, placenta and skeletal muscle.SIMILARITY Belongs to the Mediator complex subunit 30 family. UniProt Q96HR3 2 EQUAL 178 EQUAL Reactome Database ID Release 78 212398 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212398 Reactome R-HSA-212398 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212398.1 MED31 Reactome DB_ID: 212429 UniProt:Q9Y3C7 MED31 MED31 SOH1 CGI-125 FUNCTION Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP.SIMILARITY Belongs to the Mediator complex subunit 31 family. UniProt Q9Y3C7 1 EQUAL 131 EQUAL Reactome Database ID Release 78 212429 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212429 Reactome R-HSA-212429 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212429.1 TRAP coactivator complex Reactome DB_ID: 212379 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Reactome Database ID Release 78 212379 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212379 Reactome R-HSA-212379 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212379.1 Reactome Database ID Release 78 212380 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=212380 Reactome R-HSA-212380 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-212380.2 Notch-HLH transcription pathway <b>THE NOTCH-HLH TRANSCRIPTION PATHWAY:</b> <br><br> Notch signaling was first identified in Drosophila, where it has been studied in detail at the genetic, molecular, biochemical and cellular levels (reviewed in Justice, 2002; Bray, 2006; Schweisguth, 2004; Louvri, 2006). In Drosophila, Notch signaling to the nucleus is thought always to be mediated by one specific DNA binding transcription factor, Suppressor of Hairless. In mammals, the homologous genes are called CBF1 (or RBPJkappa), while in worms they are called Lag-1, so that the acronym "CSL" has been given to this conserved transcription factor family. There are at least two human CSL homologues, which are now named RBPJ and RBPJL.<br><br>CSL is an example of a bifunctional DNA-binding transcription factor that mediates repression of specific target genes in one context, but activation of the same targets in another context. This bifunctionality is mediated by the association of specific Co-Repressor complexes vs. specific Co-Activator complexes in different contexts, namely in the absence or presence of Notch signaling.<br><br>In Drosophila, Su(H) represses target gene transcription in the absence of Notch signaling, but activates target genes during Notch signaling. At least some of the mammalian CSL homologues are believed also to be bifunctional, and to mediate target gene repression in the absence of Notch signaling, and activation in the presence of Notch signaling.<br><br>Notch Co-Activator and Co-Repressor complexes: This repression is mediated by at least one specific co-repressor complexes (Co-R) bound to CSL in the absence of Notch signaling. In Drosophila, this co-repressor complex consists of at least three distinct co-repressor proteins: Hairless, Groucho, and dCtBP (Drosophila C-terminal Binding Protein). Hairless has been show to bind directly to Su(H), and Groucho and dCtBP have been shown to bind directly to Hairless (Barolo, 2002). All three of the co-repressor proteins have been shown to be necessary for proper gene regulation during Notch signaling in vivo (Nagel, 2005).<br><br>In mammals, the same general pathway and mechanisms are observed, where CSL proteins are bifunctional DNA binding transcription factors (TFs), that bind to Co-Repressor complexes to mediate repression in the absence of Notch signaling, and bind to Co-Activator complexes to mediate activation in the presence of Notch signaling. However, in mammals, there may be multiple co-repressor complexes, rather than the single Hairless co-repressor complex that has been observed in Drosophila. <br><br>During Notch signaling in all systems, the Notch transmembrane receptor is cleaved and the Notch intracellular domain (NICD) translocates to the nucleus, where it there functions as a specific transcription co-activator for CSL proteins. In the nucleus, NICD replaces the Co-R complex bound to CSL, thus resulting in de-repression of Notch target genes in the nucleus. Once bound to CSL, NICD and CSL proteins recruit an additional co-activator protein, Mastermind, to form a CSL-NICD-Mam ternary co-activator (Co-A) complex. This Co-A complex was initially thought to be sufficient to mediate activation of at least some Notch target genes. However, there now is evidence that still other co-activators and additional DNA-binding transcription factors are required in at least some contexts (reviewed in Barolo, 2002).<br><br>Mammalian CSL Corepressor Complexes: In the absence of activated Notch signaling, DNA-bound CSL proteins recruit a corepressor complex to maintain target genes in the repressed state until Notch is specifically activated. The mammalian corepressor complexes include NCOR complexes, but may also include additional corepressor proteins, such as SHARP (reviewed in Mumm, 2000 and Kovall, 2007). The exact composition of the CSL NCOR complex is not known, but in other pathways the "core" NCOR corepressor complex includes at least one NCOR protein (NCOR1, NCOR2, CIR), one Histone Deacetylase protein (HDAC1, HDAC2, HDAC3, etc), and one TBL1 protein (TBL1X, TBL1XR1) (reviewed in Rosenfeld, 2006). In some contexts, the core NCOR corepressor complex may also recruit additional corepressor proteins or complexes, such as the SIN3 complex, which consists of SIN3 (SIN3A, SIN3B), and SAP30, or other SIN3-associated proteins. An additional CSL - NCOR binding corepressor, SHARP, may also contribute to the CSL corepressor complex in some contexts (Oswald, 2002). The CSL corepressor complex also includes a bifunctional cofactor, SKIP, that is present in both CSL corepressor complexes and CSL coactivator complexes, and may function in the binding of NICD and displacement of the corepressor complex during activated Notch signaling (Zhou, 2000).<br><br>Mammalian CSL Coactivator Complexes: Upon activation of Notch signaling, cleavage of the transmembrane Notch receptor releases the Notch Intracellular Domain (NICD), which translocates to the nucleus, where it binds to CSL and displaces the corepressor complex from CSL (reviewed in Mumm, 2000 and Kovall, 2007). The resulting CSL-NICD "binary complex" then recruits an additional coactivator, Mastermind (Mam), to form a ternary complex. The ternary complex then recruits additional, more general coactivators, such as CREB Binding Protein (CBP), or the related p300 coactivator, and a number of Histone Acetytransferase (HAT) proteins, including GCN5 and PCAF (Fryer, 2002). There is evidence that Mam also can subsequently recruit specific kinases that phosphorylate NICD, to downregulate its function and turn off Notch signaling (Fryer, 2004).<br><br>Combinatorial Complexity in Transcription Cofactor Complexes: HDAC9 has at least 7 splice isoforms, with some having distinct interaction and functional properties. Isoforms 6 and 7 interact with NCOR1. Isoforms 1 and 4 interact with MEF2 (Sparrow, 1999), which is a specific DNA-binding cofactor for a subset of HLH proteins. Isoform 3 interacts with both NCOR1 and MEF2. Although many HDACs only have one or two isoforms, this complexity for HDAC9 illustrates the level of transcript complexity and functional specificity that such "general" transcriptional cofactors can have. Authored: Caudy, M, 2008-02-08 22:45:45 Edited: Caudy, M, 2008-02-08 22:45:45 LEFT-TO-RIGHT Formation of CSL NCOR corepressor complex Mammalian CSL Corepressor Complexes: In the absence of activated Notch signaling, DNA-bound CSL proteins recruit a corepressor complex to maintain target genes in the repressed state until Notch is specifically activated. The mammalian corepressor complexes include NCOR complexes, but may also include additional corepressor proteins, such as SHARP (reviewed in Mumm, 2000 and Kovall, 2007). The exact composition of the CSL NCOR complex is not known, but in other pathways the "core" NCOR corepressor complex includes at least one NCOR protein (NCOR1, NCOR2, CIR), one Histone Deacetylase protein (HDAC1, HDAC3, or certain others), and one TBL1 protein (TBL1X, TBL1XR1) (reviewed in Rosenfeld, 2006). In some contexts, the core NCOR corepressor complex may also recruit additional corepressor proteins or complexes, such as the SIN3 complex, which consists of SIN3 (SIN3A, SIN3B), and SAP30, or other SIN3-associated proteins. An additional CSL - NCOR binding corepressor, SHARP, may also contribute to the CSL corepressor complex in some contexts (Oswald, 2002). The CSL corepressor complex also includes a bifunctional cofactor, SKIP, that is present in both CSL corepressor complexes and CSL coactivator complexes, and may function in the binding of NICD and displacement of the corepressor complex during activated Notch signaling (Zhou, 2000). The formation of the CSL-NCOR corepressor complexes is modelled here as the simultaneous assembly of the various components shown. The order of addition of components is not known, and may vary in different contexts. Authored: Caudy, M, 2008-05-14 06:33:05 Reviewed: Baker, N, 2008-06-05 07:19:32 Edited: Caudy, M, 2008-02-08 22:45:45 Converted from EntitySet in Reactome TBL1 Reactome DB_ID: 350064 TBL1 TBL1X TBL1X_HUMAN Reactome DB_ID: 351644 UniProt:O60907 TBL1X TBL1X TBL1 FUNCTION F-box-like protein involved in the recruitment of the ubiquitin/19S proteasome complex to nuclear receptor-regulated transcription units (PubMed:14980219). Plays an essential role in transcription activation mediated by nuclear receptors. Probably acts as integral component of corepressor complexes that mediates the recruitment of the 19S proteasome complex, leading to the subsequent proteasomal degradation of transcription repressor complexes, thereby allowing cofactor exchange (PubMed:21240272).SUBUNIT Homotetramer; dimer of dimers (PubMed:21240272). Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1R, CORO2A and GPS2 (PubMed:10809664, PubMed:21240272). Interacts with GPS2 (when sumoylated); leading to protect GPS2 against degradation by the proteasome (PubMed:24943844). Component of a E3 ubiquitin ligase complex containing UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X (PubMed:11389839). Probably part of other corepressor complexes, that do not contain NCOR1 and NCOR2. Interacts with histones H2B, H3a and H4. Interacts with MECP2; recruits TBL1X to the heterochromatin foci (By similarity).TISSUE SPECIFICITY Ubiquitous.DOMAIN The F-box-like domain is related to the F-box domain, and apparently displays the same function as component of ubiquitin E3 ligase complexes.SIMILARITY Belongs to the WD repeat EBI family. UniProt O60907 1 EQUAL 577 EQUAL Reactome Database ID Release 78 351644 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=351644 Reactome R-HSA-351644 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-351644.1 TBL1R TBL1XR1 TBL1R_HUMAN F-box-like/WD repeat-containing protein Reactome DB_ID: 351643 UniProt:Q9BZK7 TBL1XR1 TBL1XR1 IRA1 TBLR1 FUNCTION F-box-like protein involved in the recruitment of the ubiquitin/19S proteasome complex to nuclear receptor-regulated transcription units. Plays an essential role in transcription activation mediated by nuclear receptors. Probably acts as integral component of the N-Cor corepressor complex that mediates the recruitment of the 19S proteasome complex, leading to the subsequent proteasomal degradation of N-Cor complex, thereby allowing cofactor exchange, and transcription activation.SUBUNIT Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1XR1, CORO2A and GPS2 (PubMed:11931768). Probable component of some E3 ubiquitin ligase complex. Interacts with histones H2B and H4 (PubMed:12628926). Interacts with MECP2; bridges interaction between MECP2 and NCOR1 (By similarity).TISSUE SPECIFICITY Widely expressed including the pituitary, hypothalamus, white and brown adipose tissue, muscle and liver.DOMAIN The F-box-like domain is related to the F-box domain, and apparently displays the same function as component of ubiquitin E3 ligase complexes.SIMILARITY Belongs to the WD repeat EBI family. UniProt Q9BZK7 1 EQUAL 514 EQUAL Reactome Database ID Release 78 351643 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=351643 Reactome R-HSA-351643 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-351643.1 Reactome Database ID Release 78 350064 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=350064 Reactome R-HSA-350064 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-350064.1 RBPJ Recombining binding protein suppressor of hairless SUH_HUMAN CBF1 Reactome DB_ID: 3008668 UniProt:Q06330 RBPJ RBPJ IGKJRB IGKJRB1 RBPJK RBPSUH FUNCTION Transcriptional regulator that plays a central role in Notch signaling, a signaling pathway involved in cell-cell communication that regulates a broad spectrum of cell-fate determinations. Acts as a transcriptional repressor when it is not associated with Notch proteins. When associated with some NICD product of Notch proteins (Notch intracellular domain), it acts as a transcriptional activator that activates transcription of Notch target genes. Probably represses or activates transcription via the recruitment of chromatin remodeling complexes containing histone deacetylase or histone acetylase proteins, respectively. Specifically binds to the immunoglobulin kappa-type J segment recombination signal sequence. Binds specifically to methylated DNA (PubMed:21991380). Binds to the oxygen responsive element of COX4I2 and activates its transcription under hypoxia conditions (4% oxygen) (PubMed:23303788). Negatively regulates the phagocyte oxidative burst in response to bacterial infection by repressing transcription of NADPH oxidase subunits (By similarity).SUBUNIT Interacts with activated NOTCH1, NOTCH2 or NOTCH3. Interacts with MINT/SHARP. This interaction may mediate the recruitment of large corepressor complexes containing proteins such as HDAC1, HDAC2, NCOR2, SAP30, FHL1/KYOT2 and CIR1. Interacts with EP300, MAML1 and PTF1A. Interacts with Epstein-Barr virus EBNA2, EBNA3, EBNA4 and EBNA6. Interacts with RITA1/C12orf52, leading to nuclear export, prevent the interaction between RBPJ and NICD product and subsequent down-regulation of the Notch signaling pathway. Interacts with SNW1. Interacts with CHCHD2 and CXXC5 (PubMed:23303788). Interacts with BEND6 (via BEN domain). Interacts with NKAPL (By similarity). Interacts with ZMIZ1. Interacts with RBM15 (By similarity).SIMILARITY Belongs to the Su(H) family.CAUTION Despite some similarity with the 'phage' integrase family, it has no recombinase activity. UniProt Q06330 1 EQUAL 500 EQUAL Reactome Database ID Release 78 3008668 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3008668 Reactome R-HSA-3008668 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3008668.1 Converted from EntitySet in Reactome NCOR1, NCOR2 NCOR corepressor protein Reactome DB_ID: 349716 NCOR1 Nuclear receptor corepressor 1 NCOR1_HUMAN Reactome DB_ID: 442501 UniProt:O75376 NCOR1 NCOR1 KIAA1047 FUNCTION Mediates transcriptional repression by certain nuclear receptors (PubMed:20812024). Part of a complex which promotes histone deacetylation and the formation of repressive chromatin structures which may impede the access of basal transcription factors. Participates in the transcriptional repressor activity produced by BCL6. Recruited by ZBTB7A to the androgen response elements/ARE on target genes, negatively regulates androgen receptor signaling and androgen-induced cell proliferation (PubMed:20812024). Mediates the NR1D1-dependent repression and circadian regulation of TSHB expression (By similarity). The NCOR1-HDAC3 complex regulates the circadian expression of the core clock gene ARTNL/BMAL1 and the genes involved in lipid metabolism in the liver (By similarity).SUBUNIT Forms a large corepressor complex that contains SIN3A/B and histone deacetylases HDAC1 and HDAC2. This complex associates with the thyroid receptor (TR) and the retinoid acid receptor (RAR) in the absence of ligand. Interacts directly with RARA; the interaction is facilitated with RARA trimethylation. Component of the N-Cor repressor complex, at least composed of CBFA2T3, HEXIM1, NCOR1, NCOR2, HDAC3, TBL1X, TBL1XR1, CORO2A and GPS2. Interacts with ZBTB33; the interaction serves to recruit the N-CoR complex to promoter regions containing methylated CpG dinucleotides. Interacts with TRIM28 and KDM3A. Interacts (via the RD1 domain) with BAZ1A (via its N-terminal); the interaction corepresses a number of NCOR1-regulated genes. Interacts with BCL6, C1D, DACH1, HEXIM1, HDAC7, RORA, RORC, SAP30, SIAH2, SIN3A and SIN3B. May interact with DEAF1. Interacts with RXRA. Interacts with SETD5 (By similarity). Interacts with VDR (PubMed:28698609). Interacts with ZBTB7A (PubMed:20812024). Interacts with AR (PubMed:20812024). Interacts with HDAC3 (By similarity).DOMAIN The N-terminal region contains three independent domains that are capable of mediating transcriptional repression (RD1, RD2 and RD3).DOMAIN The C-terminal region contains two separate nuclear receptor-interacting domains (ID1 and ID2), each of which contains a conserved sequence referred to as the CORNR box. This motif is necessary and sufficient for binding to unligated nuclear hormone receptors, while sequences flanking the CORNR box determine the precise nuclear hormone receptor specificity (By similarity).PTM Ubiquitinated; mediated by SIAH2 and leading to its subsequent proteasomal degradation.SIMILARITY Belongs to the N-CoR nuclear receptor corepressors family. UniProt O75376 1 EQUAL 2440 EQUAL Reactome Database ID Release 78 442501 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442501 Reactome R-HSA-442501 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-442501.1 Smrt NCOR2 Nuclear receptor corepressor 2 NCOR2_HUMAN Reactome DB_ID: 442469 UniProt:Q9Y618 NCOR2 NCOR2 CTG26 FUNCTION Transcriptional corepressor (PubMed:20812024). Mediates the transcriptional repression activity of some nuclear receptors by promoting chromatin condensation, thus preventing access of the basal transcription. Isoform 1 and isoform 4 have different affinities for different nuclear receptors. Involved in the regulation BCL6-dependent of the germinal center (GC) reactions, mainly through the control of the GC B-cells proliferation and survival. Recruited by ZBTB7A to the androgen response elements/ARE on target genes, negatively regulates androgen receptor signaling and androgen-induced cell proliferation (PubMed:20812024).SUBUNIT Forms a large corepressor complex that contains SIN3A/B and histone deacetylases HDAC1 and HDAC2. This complex associates with the thyroid (TR) and the retinoid acid receptors (RAR) in the absence of ligand, and may stabilize their interaction with TFIIB. Interacts directly with RARA in the absence of ligand; the interaction represses RARA activity. Interacts (isoform SMRT) with HDAC10. Interacts with MINT. Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1R, CORO2A and GPS2 (PubMed:10809664, PubMed:10944117, PubMed:11931768, PubMed:19858209, PubMed:21240272). Interacts with CBFA2T3 and ATXN1L. Interacts with RARB; the interaction is weak and does not repress RARB transactivational activity. Interacts with HDAC7 and C1D. Interacts with NR4A2; this interaction increases in the absence of PITX3. Interacts with BCL6 (via the BTB domain), required for BCL6 transcriptional repressor activity on a subset of target genes. Forms ternary complexes with BCOR and BCL6 on target gene promoters but, on enhancer elements, interacts with BCL6 and HDAC3 to repress proximal gene expression. May interact with DEAF1. Interacts with RXRA. Interacts with MECP2 (By similarity). Interacts with ZBTB7A (PubMed:20812024). Interacts with AR (PubMed:20812024). Interacts with TBL1Y (PubMed:30341416).TISSUE SPECIFICITY Ubiquitous. High levels of expression are detected in lung, spleen and brain.INDUCTION Regulated during cell cycle progression.DOMAIN The N-terminal region contains repression functions that are divided into three independent repression domains (RD1, RD2 and RD3). The C-terminal region contains the nuclear receptor-interacting domains that are divided in two separate interaction domains (ID1 and ID2).DOMAIN The two interaction domains (ID) contain a conserved sequence referred to as the CORNR box. This motif is required and sufficient to permit binding to unligated TR and RARS. Sequences flanking the CORNR box determine nuclear hormone receptor specificity.SIMILARITY Belongs to the N-CoR nuclear receptor corepressors family. UniProt Q9Y618 1 EQUAL 2525 EQUAL Reactome Database ID Release 78 442469 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442469 Reactome R-HSA-442469 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-442469.1 Reactome Database ID Release 78 349716 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=349716 Reactome R-HSA-349716 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-349716.1 SNW1 SKIP SNW domain-containing protein SNW1_HUMAN Reactome DB_ID: 351663 UniProt:Q13573 SNW1 SNW1 SKIIP SKIP FUNCTION Involved in pre-mRNA splicing as component of the spliceosome (PubMed:11991638, PubMed:28502770, PubMed:28076346). Is required in the specific splicing of CDKN1A pre-mRNA; the function probably involves the recruitment of U2AF2 to the mRNA. Is proposed to recruit PPIL1 to the spliceosome. May be involved in cyclin-D1/CCND1 mRNA stability through the SNARP complex which associates with both the 3'end of the CCND1 gene and its mRNA. Involved in transcriptional regulation. Modulates TGF-beta-mediated transcription via association with SMAD proteins, MYOD1-mediated transcription via association with PABPN1, RB1-mediated transcriptional repression, and retinoid-X receptor (RXR)- and vitamin D receptor (VDR)-dependent gene transcription in a cell line-specific manner probably involving coactivators NCOA1 and GRIP1. Is involved in NOTCH1-mediated transcriptional activation. Binds to multimerized forms of Notch intracellular domain (NICD) and is proposed to recruit transcriptional coactivators such as MAML1 to form an intermediate preactivation complex which associates with DNA-bound CBF-1/RBPJ to form a transcriptional activation complex by releasing SNW1 and redundant NOTCH1 NICD.FUNCTION (Microbial infection) Is recruited by HIV-1 Tat to Tat:P-TEFb:TAR RNA complexes and is involved in Tat transcription by recruitment of MYC, MEN1 and TRRAP to the HIV promoter.FUNCTION (Microbial infection) Proposed to be involved in transcriptional activation by EBV EBNA2 of CBF-1/RBPJ-repressed promoters.SUBUNIT Identified in the spliceosome C complex (PubMed:11991638, PubMed:28502770, PubMed:28076346). Associates with U4/U6-U5 tri-small nuclear ribonucleoproteins (U4/U6-U5 tri-snRNPs). Interacts SKI, SMAD2,SMAD3, RBPJ, RB1, PABPN1, MAGEA1, SIRT1, FOXN3, U2AF2, PPIL1, DAXX and ATP1B4. Interacts with VDR and RXRA; preferentially associates with VDR:RXRA heterodimers (PubMed:9632709, PubMed:12529369). Interacts with NCOR2 (PubMed:10644367). Interacts with MAML1 (PubMed:21245387). Interacts with NOTCH1 NICD; the interaction involves multimerized NOTCH1 NICD (PubMed:21245387). Forms a complex with NOTCH1 NICD and MAML1; the association is dissociated by RBPJ (PubMed:21245387). Associates with positive transcription elongation factor b (P-TEFb) (PubMed:15905409). Component of the SNARP complex which consists at least of SNIP1, SNW1, THRAP3, BCLAF1 and PNN (PubMed:18794151).SUBUNIT (Microbial infection) Interacts with human papillomavirus type-16 (HPV16) E7 protein.SUBUNIT (Microbial infection) Interacts with EBV EBNA2; EBNA2 competes with NCOR2 for interaction with SNW1.SIMILARITY Belongs to the SNW family. UniProt Q13573 2 EQUAL 536 EQUAL Reactome Database ID Release 78 351663 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=351663 Reactome R-HSA-351663 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-351663.1 Converted from EntitySet in Reactome HDAC Reactome DB_ID: 350066 HDAC10 HDA10_HUMAN Reactome DB_ID: 351579 UniProt:Q969S8 HDAC10 HDAC10 FUNCTION Polyamine deacetylase (PDAC), which acts preferentially on N(8)-acetylspermidine, and also on acetylcadaverine and acetylputrescine (PubMed:28516954). Exhibits attenuated catalytic activity toward N(1),N(8)-diacetylspermidine and very low activity, if any, toward N(1)-acetylspermidine (PubMed:28516954). Histone deacetylase activity has been observed in vitro (PubMed:11861901, PubMed:11726666, PubMed:11677242, PubMed:11739383). Has also been shown to be involved in MSH2 deacetylation (PubMed:26221039). The physiological relevance of protein/histone deacetylase activity is unclear and could be very weak (PubMed:28516954). May play a role in the promotion of late stages of autophagy, possibly autophagosome-lysosome fusion and/or lysosomal exocytosis in neuroblastoma cells (PubMed:23801752, PubMed:29968769). May play a role in homologous recombination (PubMed:21247901). May promote DNA mismatch repair (PubMed:26221039).SUBUNIT Interacts with HDAC3 (PubMed:11861901). Interacts with HDAC2 and NCOR2/SMRT (PubMed:11739383). Interacts with HSPA8/HSC70 (PubMed:23801752). Interacts with MSH2 (PubMed:26221039).TISSUE SPECIFICITY Widely expressed with high levels in liver and kidney.DISEASE In neuroblastoma cells, may promote autophagy in response to chemotherapy-induced DNA damage and efflux of chemotherapeutics via lysosomal exocytosis, hence protecting cells from cytotoxic agents (PubMed:23801752, PubMed:29968769). Expression levels may correlate with survival in neuroblastoma patients, with low levels in the tumor correlating with long-term patient survival and high expression with poor prognosis (PubMed:23801752). Therefore has been proposed as a biomarker to predict neuroblastoma chemoresistance and treatment outcome (PubMed:23801752).MISCELLANEOUS Like some other members of the HD type 2 subfamily, such as HDAC4, inhibited by the antitumor drug trichostatin A (TSA).SIMILARITY Belongs to the histone deacetylase family. HD type 2 subfamily.CAUTION Protein/histone deacetylase activity in vivo is uncertain. The 3D structure analysis of the zebrafish ortholog shows that a glutamate gatekeeper and a sterically constricted active site confer specificity for N(8)-acetylspermidine hydrolysis and disfavour acetyllysine hydrolysis. Supporting this observation, has been shown to exhibit only very low activity, if any, towards acetyl-lysine peptide substrates (PubMed:28516954). However, histone deacetylase activity has been observed in vitro (PubMed:28516954, PubMed:11861901, PubMed:11726666, PubMed:11677242, PubMed:11739383). Has also been shown to be involved in MSH2 deacetylation (PubMed:26221039). UniProt Q969S8 1 EQUAL 669 EQUAL Reactome Database ID Release 78 351579 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=351579 Reactome R-HSA-351579 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-351579.1 HDAC3 Histone deacetylase 3 HDAC3_HUMAN Reactome DB_ID: 442464 UniProt:O15379 HDAC3 HDAC3 FUNCTION Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4), and some other non-histone substrates. Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Participates in the BCL6 transcriptional repressor activity by deacetylating the H3 'Lys-27' (H3K27) on enhancer elements, antagonizing EP300 acetyltransferase activity and repressing proximal gene expression. Probably participates in the regulation of transcription through its binding to the zinc-finger transcription factor YY1; increases YY1 repression activity. Required to repress transcription of the POU1F1 transcription factor. Acts as a molecular chaperone for shuttling phosphorylated NR2C1 to PML bodies for sumoylation (PubMed:21444723, PubMed:23911289). Contributes, together with XBP1 isoform 1, to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI(3)K/mTORC2/Akt-dependent signaling pathway leading to endothelial cell (EC) survival under disturbed flow/oxidative stress (PubMed:25190803). Regulates both the transcriptional activation and repression phases of the circadian clock in a deacetylase activity-independent manner (By similarity). During the activation phase, promotes the accumulation of ubiquitinated ARNTL/BMAL1 at the E-boxes and during the repression phase, blocks FBXL3-mediated CRY1/2 ubiquitination and promotes the interaction of CRY1 and ARNTL/BMAL1 (By similarity). The NCOR1-HDAC3 complex regulates the circadian expression of the core clock gene ARTNL/BMAL1 and the genes involved in lipid metabolism in the liver (By similarity). Serves as a corepressor of RARA, causing its deacetylation and inhibition of RARE DNA element binding (PubMed:28167758). In association with RARA, plays a role in the repression of microRNA-10a and thereby in the inflammatory response (PubMed:28167758). Interacts with SETD5 (By similarity).SUBUNIT Interacts with HDAC7 and HDAC9. Forms a heterologous complex at least with YY1. Interacts with DAXX, HDAC10 and DACH1. Found in a complex with NCOR1 and NCOR2. Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1R, CORO2A and GPS2. Interacts with BCOR, MJD2A/JHDM3A, NRIP1, PRDM6 and SRY. Interacts with BTBD14B. Interacts with GLIS2. Interacts (via the DNA-binding domain) with NR2C1; the interaction recruits phosphorylated NR2C1 to PML bodies for sumoylation. Component of the Notch corepressor complex. Interacts with CBFA2T3 and NKAP. Interacts with APEX1; the interaction is not dependent on the acetylated status of APEX1. Interacts with and deacetylates MAPK14. Interacts with ZMYND15. Interacts with SMRT/NCOR2 and BCL6 on DNA enhancer elements. Interacts with INSM1 (PubMed:10655483, PubMed:10669754, PubMed:10860984, PubMed:10898795, PubMed:11006275, PubMed:11466315, PubMed:11533236, PubMed:11861901, PubMed:14525983, PubMed:14633989, PubMed:15297880, PubMed:15927959, PubMed:16569215, PubMed:18417529, PubMed:19409814, PubMed:23911289). Interacts with XBP1 isoform 1; the interaction occurs in endothelial cell (EC) under disturbed flow (PubMed:25190803). Interacts (via C-terminus) with CCAR2 (via N-terminus). Interacts with and deacetylates MEF2D. Interacts with BEND3. Interacts with NKAPL (By similarity). Interacts with DHX36; this interaction occurs in a RNA-dependent manner (PubMed:18279852). Interacts weakly with CRY1; this interaction is enhanced in the presence of FBXL3 (By similarity). Interacts with FBXL3 and ARNTL/BMAL1 (By similarity). Interacts with NCOR1 (By similarity). Interacts with RARA (PubMed:28167758).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus (HHV-5) immediate early protein IE1; this interaction decreases histone acetylation and allows transcriptional activation by the virus.TISSUE SPECIFICITY Widely expressed.INDUCTION Up-regulated by disturbed flow in umbilical vein endothelial cells in vitro (PubMed:25190803).PTM Sumoylated in vitro.SIMILARITY Belongs to the histone deacetylase family. HD type 1 subfamily. UniProt O15379 1 EQUAL 428 EQUAL Reactome Database ID Release 78 442464 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=442464 Reactome R-HSA-442464 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-442464.1 HDAC5 Histone deacetylase 5 HDAC5_HUMAN Reactome DB_ID: 3004533 UniProt:Q9UQL6 HDAC5 HDAC5 KIAA0600 FUNCTION Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation by repressing transcription of myocyte enhancer MEF2C. During muscle differentiation, it shuttles into the cytoplasm, allowing the expression of myocyte enhancer factors. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. Serves as a corepressor of RARA and causes its deacetylation (PubMed:28167758). In association with RARA, plays a role in the repression of microRNA-10a and thereby in the inflammatory response (PubMed:28167758).SUBUNIT Interacts with AHRR, BAHD1, BCOR, HDAC7, HDAC9, CTBP1, MEF2C, NCOR2, NRIP1, PHB2 and a 14-3-3 chaperone protein. Interacts with BCL6, DDIT3/CHOP, GRK5, KDM5B and MYOCD. Interacts with EP300 in the presence of TFAP2C. Interacts with ANKRA2. Interacts with CUL7 (as part of the 3M complex); negatively regulated by ANKRA2. Interacts with ZBTB7B; the interaction allows the recruitment of HDAC4 on CD8 loci for deacetylation and possible inhibition of CD8 genes expression (By similarity). Interacts with RARA (PubMed:28167758).TISSUE SPECIFICITY Ubiquitous.DOMAIN The nuclear export sequence mediates the shuttling between the nucleus and the cytoplasm.PTM Phosphorylated by AMPK, CaMK1, SIK1 and PRKD1 at Ser-259 and Ser-498. The phosphorylation is required for the export to the cytoplasm and inhibition. Phosphorylated by the PKC kinases PKN1 and PKN2, impairing nuclear import. Phosphorylated by GRK5, leading to nuclear export of HDAC5 and allowing MEF2-mediated transcription (By similarity).PTM Ubiquitinated. Polyubiquitination however does not lead to its degradation.SIMILARITY Belongs to the histone deacetylase family. HD type 2 subfamily. UniProt Q9UQL6 1 EQUAL 1122 EQUAL Reactome Database ID Release 78 3004533 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3004533 Reactome R-HSA-3004533 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3004533.1 HDAC7 Histone deacetylase 7 HDAC7_HUMAN Reactome DB_ID: 3004534 UniProt:Q8WUI4 HDAC7 HDAC7 HDAC7A FUNCTION Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation by repressing transcription of myocyte enhancer factors such as MEF2A, MEF2B and MEF2C. During muscle differentiation, it shuttles into the cytoplasm, allowing the expression of myocyte enhancer factors (By similarity). May be involved in Epstein-Barr virus (EBV) latency, possibly by repressing the viral BZLF1 gene. Positively regulates the transcriptional repressor activity of FOXP3 (PubMed:17360565). Serves as a corepressor of RARA, causing its deacetylation and inhibition of RARE DNA element binding (PubMed:28167758). In association with RARA, plays a role in the repression of microRNA-10a and thereby in the inflammatory response (PubMed:28167758).SUBUNIT Interacts with HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, NCOR1, NCOR2, SIN3A, SIN3B, RBBP4, RBBP7, MTA1L1, SAP30 and MBD3. Interacts with the 14-3-3 protein YWHAE, MEF2A, MEF2B and MEF2C (By similarity). Interacts with KAT5 and EDNRA. Interacts with KDM5B. Interacts with ZMYND15 (By similarity). Interacts with PML (isoform PML-4). Interacts with FOXP3. Interacts with RARA (PubMed:28167758).DOMAIN The nuclear export sequence mediates the shuttling between the nucleus and the cytoplasm.PTM May be phosphorylated by CaMK1. Phosphorylated by the PKC kinases PKN1 and PKN2, impairing nuclear import. Phosphorylation at Ser-155 by MARK2, MARK3 and PRKD1 promotes interaction with 14-3-3 proteins and export from the nucleus. Phosphorylation at Ser-155 is a prerequisite for phosphorylation at Ser-181.MISCELLANEOUS Its activity is inhibited by Trichostatin A (TSA), a known histone deacetylase inhibitor.SIMILARITY Belongs to the histone deacetylase family. HD type 2 subfamily. UniProt Q8WUI4 1 EQUAL 952 EQUAL Reactome Database ID Release 78 3004534 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3004534 Reactome R-HSA-3004534 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3004534.1 HDAC9 Histone deacetylase 9 HDAC9_HUMAN Reactome DB_ID: 3004554 UniProt:Q9UKV0 HDAC9 HDAC9 HDAC7 HDAC7B HDRP KIAA0744 MITR FUNCTION Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Represses MEF2-dependent transcription.FUNCTION Isoform 3 lacks active site residues and therefore is catalytically inactive. Represses MEF2-dependent transcription by recruiting HDAC1 and/or HDAC3. Seems to inhibit skeletal myogenesis and to be involved in heart development. Protects neurons from apoptosis, both by inhibiting JUN phosphorylation by MAPK10 and by repressing JUN transcription via HDAC1 recruitment to JUN promoter.ACTIVITY REGULATION Inhibited by Trichostatin A (TSA) and suberoylanilide hydroxamic acid.SUBUNIT Homodimer. Interacts with CTBP1. The phosphorylated form interacts with 14-3-3 (By similarity). Interacts with HDAC1 and HDAC3, and probably with HDAC4 and HDAC5. Interacts with MEF2, MAPK10, ETV6, NCOR1 and BCL6. Interacts with FOXP3 in the absence of T-cell stimulation.TISSUE SPECIFICITY Broadly expressed, with highest levels in brain, heart, muscle and testis. Isoform 3 is present in human bladder carcinoma cells (at protein level).PTM Phosphorylated on Ser-220 and Ser-450; which promotes 14-3-3-binding, impairs interaction with MEF2, and antagonizes antimyogenic activity. Phosphorylated on Ser-240; which impairs nuclear accumulation (By similarity). Isoform 7 is phosphorylated on Tyr-1010. Phosphorylated by the PKC kinases PKN1 and PKN2, impairing nuclear import.PTM Sumoylated.DISEASE A chromosomal aberration involving HDAC9 is found in a family with Peters anomaly. Translocation t(1;7)(q41;p21) with TGFB2 resulting in lack of HDAC9 protein.SIMILARITY Belongs to the histone deacetylase family. HD type 2 subfamily. UniProt Q9UKV0 1 EQUAL 1011 EQUAL Reactome Database ID Release 78 3004554 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3004554 Reactome R-HSA-3004554 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3004554.1 HDAC11 HDA11_HUMAN Histone deacetylase 11 Reactome DB_ID: 351590 UniProt:Q96DB2 HDAC11 HDAC11 FUNCTION Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes.SUBUNIT Interacts with HDAC6.TISSUE SPECIFICITY Weakly expressed in most tissues. Strongly expressed in brain, heart, skeletal muscle, kidney and testis.MISCELLANEOUS Its activity is inhibited by trapoxin, a known histone deacetylase inhibitor.SIMILARITY Belongs to the histone deacetylase family. UniProt Q96DB2 1 EQUAL 347 EQUAL Reactome Database ID Release 78 351590 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=351590 Reactome R-HSA-351590 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-351590.1 HDAC4 HDAC4_HUMAN Histone deacetylase 4 Reactome DB_ID: 351581 UniProt:P56524 HDAC4 HDAC4 KIAA0288 FUNCTION Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. Deacetylates HSPA1A and HSPA1B at 'Lys-77' leading to their preferential binding to co-chaperone STUB1 (PubMed:27708256).SUBUNIT Homodimer. Homodimerization via its N-terminal domain (PubMed:12032081). Interacts with MEF2A (PubMed:10487761). Interacts with MEF2C and MEF2D (PubMed:10523670). Interacts with AHRR (By similarity). Interacts with NR2C1 (PubMed:11463856). Interacts with HDAC7 (By similarity). Interacts with a 14-3-3 chaperone protein in a phosphorylation dependent manner (PubMed:10958686). Interacts with BTBD14B (By similarity). Interacts with KDM5B (PubMed:17373667). Interacts with MYOCD (By similarity). Interacts with MORC2 (PubMed:20110259). Interacts (via PxLPxI/L motif) with ANKRA2 (via ankyrin repeats). Interacts with CUL7 (as part of the 3M complex); negatively regulated by ANKRA2 (PubMed:25752541). Interacts with EP300 in the presence of TFAP2C (PubMed:24413532). Interacts with HSPA1A and HSPA1B leading to their deacetylation at 'Lys-77' (PubMed:27708256). Interacts with ZBTB7B; the interaction allows the recruitment of HDAC4 on CD8 loci for deacetylation and possible inhibition of CD8 genes expression (By similarity). Interacts with DHX36 (By similarity). Interacts with SIK3; this interaction leads to HDAC4 retention in the cytoplasm (By similarity). Interacts with ZNF638 (PubMed:30487602).TISSUE SPECIFICITY Ubiquitous.DOMAIN The nuclear export sequence mediates the shuttling between the nucleus and the cytoplasm.DOMAIN The PxLPxI/L motif mediates interaction with ankyrin repeats of ANKRA2.PTM Phosphorylated by CaMK4 at Ser-246, Ser-467 and Ser-632. Phosphorylation at other residues by CaMK2D is required for the interaction with 14-3-3. Phosphorylation at Ser-350, within the PxLPxI/L motif, impairs the binding of ANKRA2 but generates a high-affinity docking site for 14-3-3.PTM Sumoylation on Lys-559 is promoted by the E3 SUMO-protein ligase RANBP2, and prevented by phosphorylation by CaMK4.SIMILARITY Belongs to the histone deacetylase family. HD type 2 subfamily. UniProt P56524 1 EQUAL 1084 EQUAL Reactome Database ID Release 78 351581 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=351581 Reactome R-HSA-351581 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-351581.1 HDAC6 HDAC6_HUMAN Reactome DB_ID: 351589 UniProt:Q9UBN7 HDAC6 HDAC6 KIAA0901 JM21 FUNCTION Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) (PubMed:10220385). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (PubMed:10220385). Histone deacetylases act via the formation of large multiprotein complexes (PubMed:10220385). In addition to histones, deacetylates other proteins: plays a central role in microtubule-dependent cell motility by mediating deacetylation of tubulin (PubMed:12024216, PubMed:20308065). Promotes deacetylation of CTTN, leading to actin polymerization, promotion of autophagosome-lysosome fusion and completion of autophagy (PubMed:30538141). Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer (PubMed:24413532). In addition to its protein deacetylase activity, plays a key role in the degradation of misfolded proteins: when misfolded proteins are too abundant to be degraded by the chaperone refolding system and the ubiquitin-proteasome, mediates the transport of misfolded proteins to a cytoplasmic juxtanuclear structure called aggresome (PubMed:17846173). Probably acts as an adapter that recognizes polyubiquitinated misfolded proteins and target them to the aggresome, facilitating their clearance by autophagy (PubMed:17846173).SUBUNIT Interacts with SIRT2 (via both phosphorylated, unphosphorylated, active or inactive forms); the interaction is necessary for the complex to interact with alpha-tubulin (PubMed:12620231, PubMed:17516032). Under proteasome impairment conditions, interacts with UBD via its histone deacetylase 1 and UBP-type zinc-finger regions (PubMed:19033385, PubMed:25422469). Interacts with BBIP1, CBFA2T3, CYLD, DDIT3/CHOP, ZMYND15, F-actin and HDAC11 (PubMed:19893491, PubMed:11533236, PubMed:11948178, PubMed:19081074, PubMed:17872950). Interacts with RIPOR2; this interaction occurs during early myogenic differentiation and prevents HDAC6 to deacetylate tubulin (PubMed:24687993). Interacts with DYSF; this interaction occurs during early myogenic differentiation (PubMed:24687993). Interacts with TPPP; inhibiting the tubulin deacetylase activity of HDAC6 (PubMed:20308065, PubMed:23093407). Interacts with DYNLL1 (PubMed:31505170). Interacts with ATP13A2; the interaction results in recruitment of HDAC6 to lysosomes to promote CTTN deacetylation (PubMed:30538141).PTM Phosphorylated by AURKA.PTM Ubiquitinated. Its polyubiquitination however does not lead to its degradation.PTM Sumoylated in vitro.SIMILARITY Belongs to the histone deacetylase family. HD type 2 subfamily. UniProt Q9UBN7 1 EQUAL 1215 EQUAL Reactome Database ID Release 78 351589 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=351589 Reactome R-HSA-351589 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-351589.1 HDAC8 Histone deacetylase 8 HDAC8_HUMAN Reactome DB_ID: 3004556 UniProt:Q9BY41 HDAC8 HDAC8 HDACL1 CDA07 FUNCTION Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Also involved in the deacetylation of cohesin complex protein SMC3 regulating release of cohesin complexes from chromatin. May play a role in smooth muscle cell contractility.ACTIVITY REGULATION Its activity is inhibited by trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), 3-(1-methyl-4-phenylacetyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamide (APHA), 4-dimethylamino-N-(6-hydroxycarbamoyethyl)benzamide-N-hydroxy-7-(4-dimethylaminobenzoyl)aminoheptanamide (MS-344), 5-(4-methyl-benzoylamino)-biphenyl-3,4'-dicarboxylic acid 3-dimethylamide 4'-hydroxyamide (CRA-A) and butyrate.SUBUNIT Interacts with PEPB2-MYH11, a fusion protein consisting of the 165 N-terminal residues of CBF-beta (PEPB2) with the tail region of MYH11 produced by the inversion Inv(16)(p13q22), a translocation associated with acute myeloid leukemia of M4EO subtype. The PEPB2-MYH1 fusion protein also interacts with RUNX1, a well known transcriptional regulator, suggesting that the interaction with HDAC8 may participate in the conversion of RUNX1 into a constitutive transcriptional repressor. Interacts with CBFA2T3. Interacts with phosphorylated SMG5/EST1B; this interaction protects SMG5 from ubiquitin-mediated degradation. Associates with alpha-SMA (smooth muscle alpha-actin).TISSUE SPECIFICITY Weakly expressed in most tissues. Expressed at higher level in heart, brain, kidney and pancreas and also in liver, lung, placenta, prostate and kidney.PTM Phosphorylated by PKA on serine 39. Phosphorylation reduces deacetylase activity observed preferentially on histones H3 and H4.SIMILARITY Belongs to the histone deacetylase family. HD type 1 subfamily. UniProt Q9BY41 1 EQUAL 377 EQUAL Reactome Database ID Release 78 3004556 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3004556 Reactome R-HSA-3004556 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3004556.1 Reactome Database ID Release 78 350066 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=350066 Reactome R-HSA-350066 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-350066.1 CSL NCOR corepressor complex RBPJ:NCOR corepressor complex Reactome DB_ID: 350052 1 1 1 1 1 Reactome Database ID Release 78 350052 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=350052 Reactome R-HSA-350052 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-350052.2 Reactome Database ID Release 78 350058 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=350058 Reactome R-HSA-350058 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-350058.1 12374742 Pubmed 2002 SHARP is a novel component of the Notch/RBP-Jkappa signalling pathway Oswald, F Kostezka, U Astrahantseff, K Bourteele, S Dillinger, K Zechner, U Ludwig, L Wilda, M Hameister, H Knöchel, W Liptay, S Schmid, RM EMBO J 21:5417-26 11112321 Pubmed 2000 Notch signaling: from the outside in Mumm, JS Kopan, R Dev Biol 228:151-65 16530045 Pubmed 2006 Crystal structure of the CSL-Notch-Mastermind ternary complex bound to DNA Wilson, JJ Kovall, RA Cell 124:985-96 16751179 Pubmed 2006 Sensors and signals: a coactivator/corepressor/epigenetic code for integrating signal-dependent programs of transcriptional response Rosenfeld, MG Lunyak, VV Glass, CK Genes Dev 20:1405-28 10713164 Pubmed 2000 SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function Zhou, S Fujimuro, M Hsieh, JJ Chen, L Miyamoto, A Weinmaster, G Hayward, SD Mol Cell Biol 20:2400-10 LEFT-TO-RIGHT Formation of CSL-NICD coactivator complex Mammalian CSL Coactivator Complexes: Upon activation of Notch signaling, cleavage of the transmembrane Notch receptor releases the Notch Intracellular Domain (NICD), which translocates to the nucleus, where it binds to CSL and displaces the corepressor complex from CSL (reviewed in Mumm, 2000 and Kovall, 2007). The resulting CSL-NICD "binary complex" then recruits an additional coactivator, Mastermind (Mam), to form a ternary complex. The ternary complex then recruits additional, more general coactivators, such as CREB Binding Protein (CBP), or the related p300 coactivator, and a number of Histone Acetytransferase (HAT) proteins, including GCN5 and PCAF (Fryer, 2002). There is evidence that Mam also can subsequently recruit specific kinases that phosphorylate NICD, to downregulate its function and turn off Notch signaling (Fryer, 2004). Authored: Caudy, M, 2008-09-05 23:43:34 Reviewed: Baker, N, 2008-06-05 07:19:32 Edited: Caudy, M, 2008-02-08 22:45:45 KAT3A CREBBP CREB-binding protein CBP_HUMAN Reactome DB_ID: 193545 UniProt:Q92793 CREBBP CREBBP CBP FUNCTION Acetylates histones, giving a specific tag for transcriptional activation (PubMed:24616510). Also acetylates non-histone proteins, like DDX21, FBL, IRF2, MAFG, NCOA3, POLR1E/PAF53 and FOXO1 (PubMed:10490106, PubMed:11154691, PubMed:12738767, PubMed:12929931, PubMed:9707565, PubMed:24207024, PubMed:28790157, PubMed:30540930). Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1. Acts as a circadian transcriptional coactivator which enhances the activity of the circadian transcriptional activators: NPAS2-ARNTL/BMAL1 and CLOCK-ARNTL/BMAL1 heterodimers (PubMed:14645221). Acetylates PCNA; acetylation promotes removal of chromatin-bound PCNA and its degradation during nucleotide excision repair (NER) (PubMed:24939902). Acetylates POLR1E/PAF53, leading to decreased association of RNA polymerase I with the rDNA promoter region and coding region (PubMed:24207024). Acetylates DDX21, thereby inhibiting DDX21 helicase activity (PubMed:28790157). Acetylates FBL, preventing methylation of 'Gln-105' of histone H2A (H2AQ104me) (PubMed:30540930). Functions as a transcriptional coactivator for SMAD4 in the TGF-beta signaling pathway (PubMed:25514493).SUBUNIT Found in a complex containing NCOA2; NCOA3; IKKA; IKKB and IKBKG. Probably part of a complex with HIF1A and EP300. Interacts with GATA1; the interaction results in acetylation and enhancement of transcriptional activity of GATA1. Interacts with MAF AND ZCCHC12. Interacts with DAXX; the interaction is dependent on CBP sumoylation and results in suppression of the transcriptional activity via recruitment of HDAC2 to DAXX (By similarity). Interacts with phosphorylated CREB1. Interacts with CITED4 (C-terminal region). Interacts (via the TAZ-type 1 domain) with HIF1A. Interacts with SRCAP, CARM1, ELF3, MLLT7/FOXO4, N4BP2, NCOA1, NCOA3, NCOA6, PCAF, DDX5, DDX17, PELP1, PML, SMAD1, SMAD2, SMAD3, SPIB and TRERF1. Interacts with KLF1; the interaction results in acetylation of KLF1 and enhancement of its transcriptional activity. Interacts with MTDH. Interacts with NFATC4. Interacts with MAFG; the interaction acetylates MAFG in the basic region and stimulates NFE2 transcriptional activity through increasing its DNA-binding activity. Interacts with IRF2; the interaction acetylates IRF2 and regulates its activity on the H4 promoter. Interacts with IRF3 (when phosphorylated); forming the dsRNA-activated factor 1 (DRAF1), a complex which activates the transcription of the type I interferon genes (PubMed:27302953). Interacts (via N-terminus) with SS18L1/CREST (via C-terminus). Interacts with MECOM. Interacts with CITED1 (via C-terminus). Interacts with FOXO1; the interaction acetylates FOXO1 and inhibits its transcriptional activity. Interacts with NPAS2, CLOCK and ARNTL/BMAL1. Interacts with ASF1A and ASF1B; this promotes histone acetylation. Interacts with acetylated TP53/p53 and with the acetylated histones H3 and H4. Interacts (via transactivation domain and C-terminus) with PCNA; the interaction occurs on chromatin in UV-irradiated damaged cells (PubMed:24939902). Interacts with DHX9 (via N-terminus); this interaction mediates association with RNA polymerase II holoenzyme and stimulates CREB-dependent transcriptional activation (PubMed:9323138). Interacts with SMAD4; negatively regulated by ZBTB7A (PubMed:25514493). Interacts with DUX4 (via C-terminus) (PubMed:26951377). Forms a complex with KMT2A and CREB1 (PubMed:23651431). Interacts with DDX3X; this interaction may facilitate HNF4A acetylation (PubMed:28128295).SUBUNIT (Microbial infection) Interacts with HTLV-1 Tax, p30II and HBZ.SUBUNIT (Microbial infection) Interacts with human herpes virus 8/HHV-8 protein vIRF-1; this interaction inhibits CREBBP binding to IRF3.SUBUNIT (Microbial infection) Interacts with HIV-1 Tat.DOMAIN The KIX domain mediates binding to HIV-1 Tat.PTM Methylation of the KIX domain by CARM1 blocks association with CREB. This results in the blockade of CREB signaling, and in activation of apoptotic response (By similarity).PTM Phosphorylated by CHUK/IKKA at Ser-1382 and Ser-1386; these phosphorylations promote cell growth by switching the binding preference of CREBBP from TP53 to NF-kappa-B.PTM Sumoylation negatively regulates transcriptional activity via the recruitment of DAAX.PTM Autoacetylation is required for binding to protein substrates, such as acetylated histones and acetylated TP53/p53.DISEASE Chromosomal aberrations involving CREBBP may be a cause of acute myeloid leukemias. Translocation t(8;16)(p11;p13) with KAT6A; translocation t(11;16)(q23;p13.3) with KMT2A/MLL1; translocation t(10;16)(q22;p13) with KAT6B. KAT6A-CREBBP may induce leukemia by inhibiting RUNX1-mediated transcription. UniProt Q92793 1 EQUAL 2442 EQUAL Reactome Database ID Release 78 193545 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=193545 Reactome R-HSA-193545 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-193545.1 Converted from EntitySet in Reactome MAML Reactome DB_ID: 212357 MAML1 Reactome DB_ID: 212416