BioPAX pathway converted from "Cell Cycle Checkpoints" in the Reactome database. Cell Cycle Checkpoints A hallmark of the human cell cycle in normal somatic cells is its precision. This remarkable fidelity is achieved by a number of signal transduction pathways, known as checkpoints, which monitor cell cycle progression ensuring an interdependency of S-phase and mitosis, the integrity of the genome and the fidelity of chromosome segregation.<p>Checkpoints are layers of control that act to delay CDK activation when defects in the division program occur. As the CDKs functioning at different points in the cell cycle are regulated by different means, the various checkpoints differ in the biochemical mechanisms by which they elicit their effect. However, all checkpoints share a common hierarchy of a sensor, signal transducers, and effectors that interact with the CDKs.<p>The stability of the genome in somatic cells contrasts to the almost universal genomic instability of tumor cells. There are a number of documented genetic lesions in checkpoint genes, or in cell cycle genes themselves, which result either directly in cancer or in a predisposition to certain cancer types. Indeed, restraint over cell cycle progression and failure to monitor genome integrity are likely prerequisites for the molecular evolution required for the development of a tumor. Perhaps most notable amongst these is the p53 tumor suppressor gene, which is mutated in >50% of human tumors. Thus, the importance of the checkpoint pathways to human biology is clear. Authored: Hoffmann, I, Khanna, KK, Walworth, N, Yen, Tim, O'Donnell, M, 2005-01-01 Reviewed: Sanchez, Y, Knudsen, E, Hardwick, KG, 0000-00-00 00:00:00 Edited: Matthews, L, 0000-00-00 00:00:00 G1/S DNA Damage Checkpoints In the G1 phase there are two types of DNA damage responses, the p53-dependent and the p53-independent pathways. The p53-dependent responses inhibit CDKs through the up-regulation of genes encoding CKIs mediated by the p53 protein, whereas the p53-independent mechanisms inhibit CDKs through the inhibitory T14Y15 phosphorylation of Cdk2. Failure of DNA damage checkpoints in G1 leads to mutagenic replication of damaged templates and other replication defects. Authored: Hoffmann, I, Khanna, K, 2003-06-05 08:03:42 p53-Dependent G1/S DNA damage checkpoint The arrest at G1/S checkpoint is mediated by the action of a widely known tumor suppressor protein, p53. Loss of p53 functions, as a result of mutations in cancer prevent the G1/S checkpoint (Kuerbitz et al, 1992). P53 is rapidly induced in response to damaged DNA. A number of kinases, phosphatases, histone acetylases and ubiquitin-conjugating enzymes regulate the stability as well as transcriptional activity of p53 after DNA damage. Authored: Khanna, K, 2003-06-05 08:03:38 Edited: Joshi-Tope, G, 0000-00-00 00:00:00 p53-Dependent G1 DNA Damage Response Most of the damage-induced modifications of p53 are dependent on the ATM kinase. The first link between ATM and p53 was predicted based on the earlier studies that showed that AT cells exhibit a reduced and delayed induction of p53 following exposure to IR (Kastan et al, 1992 and Khanna and Lavin, 1993).<p>Under normal conditions, p53 is a short-lived protein. The MDM2 protein, usually interacts with p53 (Haupt et al, 1997 and Kubbutat et al, 1997), and by virtue of its E3 ubiquitin ligase activity, shuttles p53 to the cytoplasm and mediates its degradation by the ubiquitin-proteasome machinery. Upon detection of DNA damage, the ATM kinase mediates the phosphorylation of the Mdm2 protein to block its interaction with p53. Also, phosphorylation of p53 at multiple loci, by the ATM kinase and by other kinases activated by the ATM kinase, stabilizes and activates the p53 protein.<p>The p53 protein activates the transcription of cyclin-dependent kinase inhibitor, p21. p21 inactivates the CyclinE:Cdk2 complexes, and prevent entry of the cell into S phase, leading to G1 arrest. Under severe conditions, the cell may undergo apoptosis. Reviewed: Manfredi, James J Stabilization of p53 Later studies pin-pointed that a single serine (Ser-15) was phosphorylated by ATM and phosphorylation of Ser-15 was rapidly-induced in IR-treated cells and this response was ATM-dependent (Canman et al, 1998; Banin et al, 1998 and Khanna et al, 1998). ATM also regulates the phosphorylation of p53 at other sites, especially Ser-20, by activating other serine/threonine kinases in response to IR (Chehab et al, 2000; Shieh et al, 2000; Hirao et al 2000). Phosphorylation of p53 at Ser-20 interferes with p53-MDM2 interaction. MDM2 is transcriptionally activated by p53 and is a negative regulator of p53 that targets it for degradation (Haupt et al, 1997; Kubbutat et al, 1997). In addition modification of MDM2 by ATM also affects p53 stabilization (Maya et al, 2001). Reviewed: Sanchez, Y, 2008-05-07 22:09:03 Edited: Matthews, L, 2008-05-12 13:48:33 LEFT-TO-RIGHT 2.7.11.1 ATM phosphorylates TP53 at S15 In response to DNA double strand breaks, serine at position 15 of the TP53 (p53) tumor suppressor protein is rapidly phosphorylated by the ATM kinase. This serves to stabilize the p53 protein. A rise in the levels of the p53 protein induces the expression of p21 cyclin-dependent kinase inhibitor. This prevents the normal progression from G1 to S phase, thus providing a check on replication of damaged DNA (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998). Authored: Khanna, K, 2003-06-05 08:03:38 Reviewed: Sanchez, Y, 2008-05-07 22:09:03 Reviewed: Borowiec, James A, 2015-06-12 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-05-12 TP53 Tetramer Reactome DB_ID: 3209194 nucleoplasm GENE ONTOLOGY GO:0005654 TP53 p53 protein P53_HUMAN Cellular tumor antigen p53 Tumor suppressor p53 Phosphoprotein p53 Antigen NY-CO-13 Reactome DB_ID: 69488 UniProt:P04637 TP53 TP53 P53 FUNCTION Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type. Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. Its pro-apoptotic activity is activated via its interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 (PubMed:12524540). However, this activity is inhibited when the interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 is displaced by PPP1R13L/iASPP (PubMed:12524540). In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; the function is largely independent of transcription. Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seems to have an effect on cell-cycle regulation. Implicated in Notch signaling cross-over. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Isoform 2 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 inhibits isoform 1-mediated apoptosis. Regulates the circadian clock by repressing CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER2 (PubMed:24051492).SUBUNIT Forms homodimers and homotetramers (PubMed:19011621). Binds DNA as a homotetramer. Interacts with AXIN1. Probably part of a complex consisting of TP53, HIPK2 and AXIN1 (By similarity). Interacts with histone acetyltransferases EP300 and methyltransferases HRMT1L2 and CARM1, and recruits them to promoters. Interacts (via C-terminus) with TAF1; when TAF1 is part of the TFIID complex. Interacts with ING4; this interaction may be indirect. Found in a complex with CABLES1 and TP73. Interacts with HIPK1, HIPK2, and TP53INP1. Interacts with WWOX. May interact with HCV core protein. Interacts with USP7 and SYVN1. Interacts with HSP90AB1. Interacts with CHD8; leading to recruit histone H1 and prevent transactivation activity (By similarity). Interacts with ARMC10, CDKN2AIP, NUAK1, STK11/LKB1, UHRF2 and E4F1. Interacts with YWHAZ; the interaction enhances TP53 transcriptional activity. Phosphorylation of YWHAZ on 'Ser-58' inhibits this interaction. Interacts (via DNA-binding domain) with MAML1 (via N-terminus). Interacts with MKRN1. Interacts with PML (via C-terminus). Interacts with MDM2; leading to ubiquitination and proteasomal degradation of TP53. Directly interacts with FBXO42; leading to ubiquitination and degradation of TP53. Interacts (phosphorylated at Ser-15 by ATM) with the phosphatase PP2A-PPP2R5C holoenzyme; regulates stress-induced TP53-dependent inhibition of cell proliferation. Interacts with PPP2R2A. Interacts with AURKA, DAXX, BRD7 and TRIM24. Interacts (when monomethylated at Lys-382) with L3MBTL1. Isoform 1 interacts with isoform 2 and with isoform 4. Interacts with GRK5. Binds to the CAK complex (CDK7, cyclin H and MAT1) in response to DNA damage. Interacts with CDK5 in neurons. Interacts with AURKB, SETD2, UHRF2 and NOC2L. Interacts (via N-terminus) with PTK2/FAK1; this promotes ubiquitination by MDM2. Interacts with PTK2B/PYK2; this promotes ubiquitination by MDM2. Interacts with PRKCG. Interacts with PPIF; the association implicates preferentially tetrameric TP53, is induced by oxidative stress and is impaired by cyclosporin A (CsA). Interacts with SNAI1; the interaction induces SNAI1 degradation via MDM2-mediated ubiquitination and inhibits SNAI1-induced cell invasion. Interacts with KAT6A. Interacts with UBC9. Interacts with ZNF385B; the interaction is direct. Interacts (via DNA-binding domain) with ZNF385A; the interaction is direct and enhances p53/TP53 transactivation functions on cell-cycle arrest target genes, resulting in growth arrest. Interacts with ANKRD2. Interacts with RFFL and RNF34; involved in p53/TP53 ubiquitination. Interacts with MTA1 and COP1. Interacts with CCAR2 (via N-terminus). Interacts with MORC3 (PubMed:17332504). Interacts (via C-terminus) with POU4F2 isoform 1 (via C-terminus) (PubMed:17145718). Interacts (via oligomerization region) with NOP53; the interaction is direct and may prevent the MDM2-mediated proteasomal degradation of TP53 (PubMed:22522597). Interacts with AFG1L; mediates mitochondrial translocation of TP53 (PubMed:27323408). Interacts with UBD (PubMed:25422469). Interacts with TAF6 isoform 1 and isoform 4 (PubMed:20096117). Interacts with C10orf90/FATS; the interaction inhibits binding of TP53 and MDM2 (By similarity). Interacts with NUPR1; interaction is stress-dependent (PubMed:18690848). Forms a complex with EP300 and NUPR1; this complex binds CDKN1A promoter leading to transcriptional induction of CDKN1A (PubMed:18690848). Interacts with PRMT5 in response to DNA damage; the interaction is STRAP dependent (PubMed:19011621). Interacts with PPP1R13L (via SH3 domain and ANK repeats); the interaction inhibits pro-apoptotic activity of p53/TP53 (PubMed:12524540). Interacts with PPP1R13B/ASPP1 and TP53BP2/ASPP2; the interactions promotes pro-apoptotic activity (PubMed:12524540). When phosphorylated at Ser-15, interacts with DDX3X and gamma-tubulin (PubMed:28842590). Interacts with KAT7/HBO1; leading to inhibit histone acetyltransferase activity of KAT7/HBO1 (PubMed:17954561). Interacts (via N-terminus) with E3 ubiquitin-protein ligase MUL1; the interaction results in ubiquitination of cytoplasmic TP53 at Lys-24 and subsequent proteasomal degradation (PubMed:21597459). Interacts with S100A4; this interaction promotes TP53 degradation (PubMed:23752197, PubMed:32442400). Interacts with BANP (By similarity). Interacts with TTC5/STRAP; the interaction may result in increased mitochondrial-dependent apoptosis (PubMed:25168243).SUBUNIT (Microbial infection) Interacts with cancer-associated/HPV E6 viral proteins leading to ubiquitination and degradation of TP53 giving a possible model for cell growth regulation. This complex formation requires an additional factor, E6-AP, which stably associates with TP53 in the presence of E6.SUBUNIT (Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL123.SUBUNIT (Microbial infection) Interacts (via N-terminus) with human adenovirus 5 E1B-55K protein; this interaction leads to the inhibition of TP53 function and/or its degradation.SUBUNIT (Microbial infection) Interacts with Kaposi's sarcoma-associated herpesvirus/HHV-8 protein ORF45; this interaction results in the cytoplasmic localization of TP53 thereby decreasing its transcriptional activity.TISSUE SPECIFICITY Ubiquitous. Isoforms are expressed in a wide range of normal tissues but in a tissue-dependent manner. Isoform 2 is expressed in most normal tissues but is not detected in brain, lung, prostate, muscle, fetal brain, spinal cord and fetal liver. Isoform 3 is expressed in most normal tissues but is not detected in lung, spleen, testis, fetal brain, spinal cord and fetal liver. Isoform 7 is expressed in most normal tissues but is not detected in prostate, uterus, skeletal muscle and breast. Isoform 8 is detected only in colon, bone marrow, testis, fetal brain and intestine. Isoform 9 is expressed in most normal tissues but is not detected in brain, heart, lung, fetal liver, salivary gland, breast or intestine.INDUCTION Up-regulated in response to DNA damage. Isoform 2 is not induced in tumor cells in response to stress.DOMAIN The nuclear export signal acts as a transcriptional repression domain. The TADI and TADII motifs (residues 17 to 25 and 48 to 56) correspond both to 9aaTAD motifs which are transactivation domains present in a large number of yeast and animal transcription factors.PTM Acetylated. Acetylation of Lys-382 by CREBBP enhances transcriptional activity. Acetylation of Lys-382 by EP300. Deacetylation of Lys-382 by SIRT1 impairs its ability to induce proapoptotic program and modulate cell senescence. Deacetylation by SIRT2 impairs its ability to induce transcription activation in a AKT-dependent manner.PTM Phosphorylation on Ser residues mediates transcriptional activation. Phosphorylated by HIPK1 (By similarity). Phosphorylation at Ser-9 by HIPK4 increases repression activity on BIRC5 promoter. Phosphorylated on Thr-18 by VRK1. Phosphorylated on Ser-20 by CHEK2 in response to DNA damage, which prevents ubiquitination by MDM2. Phosphorylated on Ser-20 by PLK3 in response to reactive oxygen species (ROS), promoting p53/TP53-mediated apoptosis. Phosphorylated on Thr-55 by TAF1, which promotes MDM2-mediated degradation. Phosphorylated on Ser-33 by CDK7 in a CAK complex in response to DNA damage. Phosphorylated on Ser-46 by HIPK2 upon UV irradiation. Phosphorylation on Ser-46 is required for acetylation by CREBBP. Phosphorylated on Ser-392 following UV but not gamma irradiation. Phosphorylated by NUAK1 at Ser-15 and Ser-392; was initially thought to be mediated by STK11/LKB1 but it was later shown that it is indirect and that STK11/LKB1-dependent phosphorylation is probably mediated by downstream NUAK1 (PubMed:21317932). It is unclear whether AMP directly mediates phosphorylation at Ser-15. Phosphorylated on Thr-18 by isoform 1 and isoform 2 of VRK2. Phosphorylation on Thr-18 by isoform 2 of VRK2 results in a reduction in ubiquitination by MDM2 and an increase in acetylation by EP300. Stabilized by CDK5-mediated phosphorylation in response to genotoxic and oxidative stresses at Ser-15, Ser-33 and Ser-46, leading to accumulation of p53/TP53, particularly in the nucleus, thus inducing the transactivation of p53/TP53 target genes. Phosphorylated by DYRK2 at Ser-46 in response to genotoxic stress. Phosphorylated at Ser-315 and Ser-392 by CDK2 in response to DNA-damage. Phosphorylation at Ser-15 is required for interaction with DDX3X and gamma-tubulin (PubMed:28842590).PTM Dephosphorylated by PP2A-PPP2R5C holoenzyme at Thr-55. SV40 small T antigen inhibits the dephosphorylation by the AC form of PP2A.PTM May be O-glycosylated in the C-terminal basic region. Studied in EB-1 cell line.PTM Ubiquitinated by MDM2 and SYVN1, which leads to proteasomal degradation (PubMed:10722742, PubMed:12810724, PubMed:15340061, PubMed:17170702, PubMed:19880522). Ubiquitinated by RFWD3, which works in cooperation with MDM2 and may catalyze the formation of short polyubiquitin chains on p53/TP53 that are not targeted to the proteasome (PubMed:10722742, PubMed:12810724, PubMed:20173098). Ubiquitinated by MKRN1 at Lys-291 and Lys-292, which leads to proteasomal degradation (PubMed:19536131). Deubiquitinated by USP10, leading to its stabilization (PubMed:20096447). Ubiquitinated by TRIM24, RFFL, RNF34 and RNF125, which leads to proteasomal degradation (PubMed:19556538). Ubiquitination by TOPORS induces degradation (PubMed:19473992). Deubiquitination by USP7, leading to stabilization (PubMed:15053880). Isoform 4 is monoubiquitinated in an MDM2-independent manner (PubMed:15340061). Ubiquitinated by COP1, which leads to proteasomal degradation (PubMed:19837670). Ubiquitination and subsequent proteasomal degradation is negatively regulated by CCAR2 (PubMed:25732823). Polyubiquitinated by C10orf90/FATS, polyubiquitination is 'Lys-48'-linkage independent and non-proteolytic, leading to TP53 stabilization (By similarity). Polyubiquitinated by MUL1 at Lys-24 which leads to proteasomal degradation (PubMed:21597459).PTM Monomethylated at Lys-372 by SETD7, leading to stabilization and increased transcriptional activation (PubMed:15525938, PubMed:16415881). Monomethylated at Lys-370 by SMYD2, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity (PubMed:17108971). Lys-372 monomethylation prevents interaction with SMYD2 and subsequent monomethylation at Lys-370 (PubMed:17108971). Dimethylated at Lys-373 by EHMT1 and EHMT2 (PubMed:20118233). Monomethylated at Lys-382 by KMT5A, promoting interaction with L3MBTL1 and leading to repress transcriptional activity (PubMed:17707234). Dimethylation at Lys-370 and Lys-382 diminishes p53 ubiquitination, through stabilizing association with the methyl reader PHF20 (PubMed:22864287). Demethylation of dimethylated Lys-370 by KDM1A prevents interaction with TP53BP1 and represses TP53-mediated transcriptional activation (PubMed:17805299). Monomethylated at Arg-333 and dimethylated at Arg-335 and Arg-337 by PRMT5; methylation is increased after DNA damage and might possibly affect TP53 target gene specificity (PubMed:19011621).PTM Sumoylated with SUMO1. Sumoylated at Lys-386 by UBC9.DISEASE TP53 is found in increased amounts in a wide variety of transformed cells. TP53 is frequently mutated or inactivated in about 60% of cancers. TP53 defects are found in Barrett metaplasia a condition in which the normally stratified squamous epithelium of the lower esophagus is replaced by a metaplastic columnar epithelium. The condition develops as a complication in approximately 10% of patients with chronic gastroesophageal reflux disease and predisposes to the development of esophageal adenocarcinoma.SIMILARITY Belongs to the p53 family.CAUTION Interaction with BANP was reported to enhance phosphorylation on Ser-15 upon ultraviolet irradiation (PubMed:15701641). However, the publication has been retracted due to image duplication and manipulation. Interaction with BANP has been confirmed in mouse studies (By similarity). Phosphorylation at Ser-15 has been confirmed by other studies (PubMed:10570149, PubMed:11554766, PubMed:16219768, PubMed:15866171, PubMed:17317671, PubMed:17954561, PubMed:20959462, PubMed:25772236). Its nuclear and cytoplasmic localization has been confirmed by other studies (PubMed:15340061, PubMed:17170702, PubMed:19011621, PubMed:21597459, PubMed:22726440, PubMed:17591690, PubMed:18206965). Homo sapiens NCBI Taxonomy 9606 UniProt P04637 1 EQUAL 393 EQUAL Reactome Database ID Release 81 69488 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=69488 Reactome R-HSA-69488 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-69488.1 Reactome http://www.reactome.org 4 Reactome Database ID Release 81 3209194 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=3209194 Reactome R-HSA-3209194 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-3209194.1 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 81 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 additional information MI MI:0361 4 p-S15-TP53 Tetramer Reactome DB_ID: 349474 p-S15-TP53 p53 ser-15 phosphorylated Cellular tumor antigen p53 Tumor suppressor p53 Phosphoprotein p53 Antigen NY-CO-13 Reactome DB_ID: 69507 15 EQUAL O-phospho-L-serine MOD MOD:00046 1 EQUAL 393 EQUAL Reactome Database ID Release 81 69507 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=69507 Reactome R-HSA-69507 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-69507.1 4 Reactome Database ID Release 81 349474 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=349474 Reactome R-HSA-349474 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-349474.1 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 81 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 4 ACTIVATION p-S1981,Ac-K3016-ATM Reactome DB_ID: 5693527 UniProt:Q13315 ATM ATM FUNCTION Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates 'Ser-139' of histone variant H2AX at double strand breaks (DSBs), thereby regulating DNA damage response mechanism. Also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes. After the introduction of DNA breaks by the RAG complex on one immunoglobulin allele, acts by mediating a repositioning of the second allele to pericentromeric heterochromatin, preventing accessibility to the RAG complex and recombination of the second allele. Also involved in signal transduction and cell cycle control. May function as a tumor suppressor. Necessary for activation of ABL1 and SAPK. Phosphorylates DYRK2, CHEK2, p53/TP53, FBXW7, FANCD2, NFKBIA, BRCA1, CTIP, nibrin (NBN), TERF1, UFL1, RAD9, UBQLN4 and DCLRE1C (PubMed:9843217, PubMed:9733515, PubMed:10550055, PubMed:10766245, PubMed:10839545, PubMed:10910365, PubMed:10802669, PubMed:10973490, PubMed:11375976, PubMed:12086603, PubMed:15456891, PubMed:19965871, PubMed:30612738, PubMed:30886146, PubMed:26774286). May play a role in vesicle and/or protein transport. Could play a role in T-cell development, gonad and neurological function. Plays a role in replication-dependent histone mRNA degradation. Binds DNA ends. Phosphorylation of DYRK2 in nucleus in response to genotoxic stress prevents its MDM2-mediated ubiquitination and subsequent proteasome degradation. Phosphorylates ATF2 which stimulates its function in DNA damage response. Phosphorylates ERCC6 which is essential for its chromatin remodeling activity at DNA double-strand breaks (PubMed:29203878). Phosphorylates TTC5/STRAP at 'Ser-203' in the cytoplasm in response to DNA damage, which promotes TTC5/STRAP nuclear localization (PubMed:15448695).ACTIVITY REGULATION Inhibited by wortmannin.SUBUNIT Homodimer (PubMed:28508083). Dimers or tetramers in inactive state. On DNA damage, autophosphorylation dissociates ATM into monomers rendering them catalytically active. Binds p53/TP53, ABL1, BRCA1, NBN/nibrin and TERF1. Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBN protein complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains. Interacts with RAD17; DNA damage promotes the association. Interacts with EEF1E1; the interaction, induced on DNA damage, up-regulates TP53. Interacts with DCLRE1C, KAT8, KAT5, NABP2, ATMIN and CEP164. Interacts with AP2B1 and AP3B2; the interaction occurs in cytoplasmic vesicles (By similarity). Interacts with TELO2 and TTI1. Interacts with DDX1. Interacts with BRAT1. Interacts with CYREN (via XLF motif) (By similarity).TISSUE SPECIFICITY Found in pancreas, kidney, skeletal muscle, liver, lung, placenta, brain, heart, spleen, thymus, testis, ovary, small intestine, colon and leukocytes.INDUCTION By ionizing radiation.DOMAIN The FATC domain is required for interaction with KAT5.PTM Phosphorylated by NUAK1/ARK5 (PubMed:12409306). Autophosphorylation on Ser-367, Ser-1893, Ser-1981 correlates with DNA damage-mediated activation of the kinase (PubMed:12556884, PubMed:16141325, PubMed:16858402, PubMed:21144835, PubMed:27664052). During the late stages of DNA damage response, dephosphorylated following deacetylation by SIRT7, leading to ATM deactivation (PubMed:30944854).PTM Acetylation, on DNA damage, is required for activation of the kinase activity, dimer-monomer transition, and subsequent autophosphorylation on Ser-1981 (PubMed:12556884, PubMed:16141325, PubMed:16858402, PubMed:17923702, PubMed:21144835). Acetylated in vitro by KAT5/TIP60 (PubMed:16141325). Deacetylated by SIRT7 during the late stages of DNA damage response, promoting ATM dephosphorylation and subsequent deactivation (PubMed:30944854).DISEASE Defects in ATM may contribute to T-cell acute lymphoblastic leukemia (TALL) and T-prolymphocytic leukemia (TPLL). TPLL is characterized by a high white blood cell count, with a predominance of prolymphocytes, marked splenomegaly, lymphadenopathy, skin lesions and serous effusion. The clinical course is highly aggressive, with poor response to chemotherapy and short survival time. TPLL occurs both in adults as a sporadic disease and in younger AT patients.DISEASE Defects in ATM may contribute to B-cell non-Hodgkin lymphomas (BNHL), including mantle cell lymphoma (MCL).DISEASE Defects in ATM may contribute to B-cell chronic lymphocytic leukemia (BCLL). BCLL is the commonest form of leukemia in the elderly. It is characterized by the accumulation of mature CD5+ B-lymphocytes, lymphadenopathy, immunodeficiency and bone marrow failure.SIMILARITY Belongs to the PI3/PI4-kinase family. ATM subfamily. UniProt Q13315 1981 EQUAL 3016 EQUAL N6-acetyl-L-lysine MOD MOD:00064 1 EQUAL 3056 EQUAL Reactome Database ID Release 81 5693527 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=5693527 Reactome R-HSA-5693527 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-5693527.1 GENE ONTOLOGY GO:0004674 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 81 5693530 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=5693530 Reactome Database ID Release 81 5693609 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=5693609 Reactome R-HSA-5693609 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-5693609.3 9843217 Pubmed 1998 ATM associates with and phosphorylates p53: mapping the region of interaction. Khanna, Kum Kum Keating, KE Kozlov, S Scott, S Gatei, M Hobson, K Taya, Y Gabrielli, B Chan, D Lees-Miller, SP Lavin, MF Nat Genet 20:398-400 9733515 Pubmed 1998 Activation of the ATM kinase by ionizing radiation and phosphorylation of p53. Canman, CE Lim, DS Taya, Y Tamai, K Sakaguchi, K Appella, E Kastan, MB Siliciano, JD Science 281:1677-9 9733514 Pubmed 1998 Enhanced phosphorylation of p53 by ATM in response to DNA damage. Banin, S Moyal, L Shieh, S Taya, Y Anderson, CW Chessa, L Smorodinsky, NI Prives, C Reiss, Y Shiloh, Y Ziv, Y Science 281:1674-7 LEFT-TO-RIGHT 2.7.11.1 CHEK2 phosphorylates TP53 Phosphorylation of p53 by ATM-activated Chk2 CHEK2 (Chk2) phosphorylates TP53 (p53) at serine residue S20 (Hirao et al. 2000, Shieh et al. 2000, Chehab et al. 2000). Phosphorylation of TP53 at serine residue S20 is necessary for DNA damage-induced TP53 stabilization as it compromises the interaction of TP53 with the ubiquitin ligase MDM2 (Chehab et al. 1999, Chehab et al. 2000). S20 phosphorylation is also required for the induction of TP53-dependent transcripts in response to DNA damage (Hirao et al. 2000). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 4 4 p-S15,S20-TP53 Tetramer Reactome DB_ID: 3222171 p-S15,S20-TP53 Reactome DB_ID: 69683 20 EQUAL 1 EQUAL 393 EQUAL Reactome Database ID Release 81 69683 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=69683 Reactome R-HSA-69683 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-69683.1 4 Reactome Database ID Release 81 3222171 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=3222171 Reactome R-HSA-3222171 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-3222171.1 ACTIVATION p-S,3T-CHEK2 p-T68,S379,T383,T387-CHEK2 Reactome DB_ID: 5683784 UniProt:O96017 CHEK2 CHEK2 CDS1 CHK2 RAD53 FUNCTION Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks. May also negatively regulate cell cycle progression during unperturbed cell cycles. Following activation, phosphorylates numerous effectors preferentially at the consensus sequence [L-X-R-X-X-S/T]. Regulates cell cycle checkpoint arrest through phosphorylation of CDC25A, CDC25B and CDC25C, inhibiting their activity. Inhibition of CDC25 phosphatase activity leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. May also phosphorylate NEK6 which is involved in G2/M cell cycle arrest. Regulates DNA repair through phosphorylation of BRCA2, enhancing the association of RAD51 with chromatin which promotes DNA repair by homologous recombination. Also stimulates the transcription of genes involved in DNA repair (including BRCA2) through the phosphorylation and activation of the transcription factor FOXM1. Regulates apoptosis through the phosphorylation of p53/TP53, MDM4 and PML. Phosphorylation of p53/TP53 at 'Ser-20' by CHEK2 may alleviate inhibition by MDM2, leading to accumulation of active p53/TP53. Phosphorylation of MDM4 may also reduce degradation of p53/TP53. Also controls the transcription of pro-apoptotic genes through phosphorylation of the transcription factor E2F1. Tumor suppressor, it may also have a DNA damage-independent function in mitotic spindle assembly by phosphorylating BRCA1. Its absence may be a cause of the chromosomal instability observed in some cancer cells. Promotes the CCAR2-SIRT1 association and is required for CCAR2-mediated SIRT1 inhibition (PubMed:25361978).FUNCTION (Microbial infection) Phosphorylates herpes simplex virus 1/HHV-1 protein ICP0 and thus activates its SUMO-targeted ubiquitin ligase activity.ACTIVITY REGULATION Activated through phosphorylation at Thr-68 by ATM in response to DNA double-strand breaks. Activation is modulated by several mediators including MDC1 and TP53BP1. Induces homodimerization with exchange of the T-loop/activation segment between protomers and transphosphorylation of the protomers. The autophosphorylated kinase dimer is fully active. Negatively regulated by PPM1D through dephosphorylation of Thr-68.SUBUNIT Homodimer. Homodimerization is part of the activation process but the dimer may dissociate following activation. Interacts with PML. Interacts with TP53. Interacts with RB1; phosphorylates RB1. Interacts with BRCA1. Interacts (phosphorylated at Thr-68) with MDC1; requires ATM-mediated phosphorylation of CHEK2. Interacts with TP53BP1; modulates CHEK2 phosphorylation at Thr-68 in response to ionizing radiation. Interacts with CDC25A; phosphorylates CDC25A and mediates its degradation in response to ionizing radiation. Interacts with CUL1; mediates CHEK2 ubiquitination and regulation. Interacts with CDKN2AIP. Interacts (via protein kinase domain) with CCAR2 (via N-terminus). Interacts with SIRT1.TISSUE SPECIFICITY High expression is found in testis, spleen, colon and peripheral blood leukocytes. Low expression is found in other tissues.PTM Phosphorylated. Phosphorylated at Ser-73 by PLK3 in response to DNA damage, promoting phosphorylation at Thr-68 by ATM and the G2/M transition checkpoint. Phosphorylation at Thr-68 induces homodimerization. Autophosphorylates at Thr-383 and Thr-387 in the T-loop/activation segment upon dimerization to become fully active and phosphorylate its substrates like for instance CDC25C. DNA damage-induced autophosphorylation at Ser-379 induces CUL1-mediated ubiquitination and regulates the pro-apoptotic function. Phosphorylation at Ser-456 also regulates ubiquitination. Phosphorylated by PLK4.PTM Ubiquitinated. CUL1-mediated ubiquitination regulates the pro-apoptotic function. Ubiquitination may also regulate protein stability. Ubiquitinated by RNF8 via 'Lys-48'-linked ubiquitination.SIMILARITY Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CHK2 subfamily. UniProt O96017 68 EQUAL O-phospho-L-threonine MOD MOD:00047 379 EQUAL 383 EQUAL 387 EQUAL 1 EQUAL 543 EQUAL Reactome Database ID Release 81 5683784 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=5683784 Reactome R-HSA-5683784 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-5683784.1 Reactome Database ID Release 81 5683804 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=5683804 Reactome Database ID Release 81 69685 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=69685 Reactome R-HSA-69685 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-69685.3 10570149 Pubmed 1999 Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage Chehab, N H Malikzay, A Stavridi, E S Halazonetis, T D Proc. Natl. Acad. Sci. U.S.A. 96:13777-82 10673501 Pubmed 2000 The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Shieh, SY Ahn, J Tamai, K Taya, Y Prives, C Genes Dev 14:289-300 10673500 Pubmed 2000 Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53. Chehab, NH Malikzay, A Appel, M Halazonetis, TD Genes Dev 14:278-88 10710310 Pubmed 2000 DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Hirao, A Kong, YY Matsuoka, S Wakeham, A Ruland, J Yoshida, H Liu, D Elledge, SJ Mak, TW Science 287:1824-7 LEFT-TO-RIGHT 2.7.11.1 ATM phosphorylates MDM2 ATM phosphorylates MDM2 on three serine residues (S386, S395, S407) and one threonine residue (T419) in vicinity to the RING domain. ATM-mediated phosphorylation of MDM2 in response to DNA damage (DNA double strand breaks) prevents MDM2 dimerization, binding of TP53 (p53) and MDM2-mediated ubiquitination of TP53 (Cheng et al. 2009, Cheng et al. 2011). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 4 p-MDM2 p-S166,S188-MDM2 p-S166,188-MDM2 Phospho-MDM2 Reactome DB_ID: 6793669 UniProt:Q00987 MDM2 MDM2 FUNCTION E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as a ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and SNAI1 and promotes them to proteasomal degradation (PubMed:12821780, PubMed:15053880, PubMed:15195100, PubMed:15632057, PubMed:16337594, PubMed:17290220, PubMed:19098711, PubMed:19219073, PubMed:19837670, PubMed:19965871, PubMed:20173098, PubMed:20385133, PubMed:20858735, PubMed:22128911). Ubiquitinates DCX, leading to DCX degradation and reduction of the dendritic spine density of olfactory bulb granule cells (By similarity). Ubiquitinates DLG4, leading to proteasomal degradation of DLG4 which is required for AMPA receptor endocytosis (By similarity). Negatively regulates NDUFS1, leading to decreased mitochondrial respiration, marked oxidative stress, and commitment to the mitochondrial pathway of apoptosis (PubMed:30879903). Binds NDUFS1 leading to its cytosolic retention rather than mitochondrial localization resulting in decreased supercomplex assembly (interactions between complex I and complex III), decreased complex I activity, ROS production, and apoptosis (PubMed:30879903).SUBUNIT Interacts with p53/TP53, TP73/p73, RBL5 and RP11. Binds specifically to RNA. Can interact with RB1, E1A-associated protein EP300 and the E2F1 transcription factor. Forms a ternary complex with p53/TP53 and WWOX. Interacts with CDKN2AIP, RFWD3, USP7, PYHIN1, and RBBP6. Interacts with ARRB1 and ARRB2. Interacts with PSMA3. Found in a trimeric complex with MDM2, MDM4 and USP2. Interacts with USP2 (via N-terminus and C-terminus). Interacts with MDM4. Part of a complex with MDM2, DAXX, RASSF1 and USP7. Part of a complex with DAXX, MDM2 and USP7. Interacts directly with DAXX and USP7. Interacts (via C-terminus) with RASSF1 isoform A (via N-terminus); the interaction is independent of TP53. Interacts with APEX1; leading to its ubiquitination and degradation. Interacts with RYBP; this inhibits ubiquitination of TP53. Identified in a complex with RYBP and p53/TP53. Also component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in regulating p53/TP53 stabilization and activity. Binds directly both p53/TP53 and TRIM28. Component of the TRIM28/KAP1-ERBB4-MDM2 complex involved in connecting growth factor responses with DNA damage. Interacts directly with both TRIM28 and ERBB4 in the complex. Interacts with DYRK2. Interacts with IGF1R. Interacts with TRIM13; the interaction ubiquitinates MDM2 leading to its proteasomal degradation. Interacts with SNAI1; this interaction promotes SNAI1 ubiquitination. Interacts with NOTCH1 (via intracellular domain). Interacts with FHIT. Interacts with RFFL and RNF34; the interaction stabilizes MDM2. Interacts with CDK5RAP3 and CDKN2A/ARF; form a ternary complex involved in regulation of p53/TP53 (PubMed:16173922). Interacts with MTA1. Interacts with AARB2. Interacts with MTBP. Interacts with PML. Interacts with TBRG1. Interacts with the 5S RNP which is composed of the 5S RNA, RPL5 and RPL11; the interaction is direct, occurs in the nucleoplasm and negatively regulates MDM2-mediated TP53 ubiquitination and degradation (PubMed:15195100, PubMed:24120868). Interacts with ADGRB1; the interaction results in inhibition of MDM2-mediated ubiquitination and degradation of DLG4/PSD95, promoting DLG4 stability and regulating synaptic plasticity (By similarity). Interacts with RPL23A; this interaction may promote p53/TP53 polyubiquitination (PubMed:26203195). Interacts with NDUFS1 (PubMed:30879903).SUBUNIT (Microbial infection) Interacts with herpes virus 8 protein v-IRF4.SUBUNIT (Microbial infection) Interacts with and ubiquitinates HIV-1 Tat.TISSUE SPECIFICITY Ubiquitous. Isoform Mdm2-A, isoform Mdm2-B, isoform Mdm2-C, isoform Mdm2-D, isoform Mdm2-E, isoform Mdm2-F and isoform Mdm2-G are observed in a range of cancers but absent in normal tissues.INDUCTION By DNA damage.DOMAIN Region I is sufficient for binding p53 and inhibiting its G1 arrest and apoptosis functions. It also binds p73 and E2F1. Region II contains most of a central acidic region required for interaction with ribosomal protein L5 and a putative C4-type zinc finger. The RING finger domain which coordinates two molecules of zinc interacts specifically with RNA whether or not zinc is present and mediates the heterooligomerization with MDM4. It is also essential for its ubiquitin ligase E3 activity toward p53 and itself.PTM Phosphorylation on Ser-166 by SGK1 activates ubiquitination of p53/TP53. Phosphorylated at multiple sites near the RING domain by ATM upon DNA damage; this prevents oligomerization and E3 ligase processivity and impedes constitutive p53/TP53 degradation.PTM Autoubiquitination leads to proteasomal degradation; resulting in p53/TP53 activation it may be regulated by SFN. Also ubiquitinated by TRIM13. Deubiquitinated by USP2 leads to its accumulation and increases deubiquitination and degradation of p53/TP53. Deubiquitinated by USP7 leading to its stabilization.POLYMORPHISM A polymorphism in the MDM2 promoter is associated with susceptibility to accelerated tumor formation in both hereditary and sporadic cancers [MIM:614401]. It also contributes to susceptibility to Li-Fraumeni syndrome, in patients carrying a TP53 germline mutation.DISEASE Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding.MISCELLANEOUS MDM2 RING finger mutations that failed to ubiquitinate p53 in vitro did not target p53 for degradation when expressed in cells.SIMILARITY Belongs to the MDM2/MDM4 family.CAUTION Was reported to interact with UBXN6 but the corresponding article has been retracted (PubMed:18768758).CAUTION A report observed N-glycosylation at Asn-349 (PubMed:19139490). However, as the protein is not extracellular, additional evidence is required to confirm this result. UniProt Q00987 166 EQUAL 188 EQUAL 1 EQUAL 491 EQUAL Reactome Database ID Release 81 6793669 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=6793669 Reactome R-HSA-6793669 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-6793669.1 p-5S,T-MDM2 p-S166,S188,S386,S395,S407,T419-MDM2 Reactome DB_ID: 6804954 386 EQUAL 395 EQUAL 407 EQUAL 419 EQUAL 1 EQUAL 491 EQUAL Reactome Database ID Release 81 6804954 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=6804954 Reactome R-HSA-6804954 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-6804954.1 4 ACTIVATION Reactome Database ID Release 81 6804955 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=6804955 Reactome R-HSA-6804955 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-6804955.2 21986495 Pubmed 2011 Regulation of MDM2 E3 ligase activity by phosphorylation after DNA damage Cheng, Qian Cross, Brittany Li, Baozong Chen, Lihong Li, Zhenyu Chen, Jiandong Mol. Cell. Biol. 31:4951-63 19816404 Pubmed 2009 ATM activates p53 by regulating MDM2 oligomerization and E3 processivity Cheng, Qian Chen, Lihong Li, Zhenyu Lane, William S Chen, Jiandong EMBO J. 28:3857-67 LEFT-TO-RIGHT 2.7.11.1 Phosphorylation of MDM4 by ATM Human MDM4 (MDMX) is phosphorylated on serine residue S403 by ATM. This site is important for MDM2-mediated ubiquitination of MDM4 after induction of double strand DNA breaks (Pereg et al. 2005, Chen et al. 2005). Authored: Matthews, L, 2008-03-31 10:45:58 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Matthews, L, 2008-05-12 14:39:01 p-S166,S188-MDM2:MDM4 Reactome DB_ID: 6804932 MDM4 Mdmx Reactome DB_ID: 349430 UniProt:O15151 MDM4 MDM4 MDMX FUNCTION Along with MDM2, contributes to TP53 regulation (PubMed:32300648). Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions.SUBUNIT Interacts with MDM2 (PubMed:16163388, PubMed:19838211, PubMed:32300648). Interacts with TP53, TP73 and USP2. Found in a trimeric complex with USP2, MDM2 and MDM4. Interacts (phosphorylated) with YWHAG; negatively regulates MDM4 activity toward TP53.TISSUE SPECIFICITY Expressed in all tissues tested with high levels in thymus.INDUCTION Down-regulated by cisplatin (at protein level).DOMAIN Region I is sufficient for binding TP53 and inhibiting its G1 arrest and apoptosis functions. It also binds TP73. Region II contains most of a central acidic region and a putative C4-type zinc finger. The RING finger domain which coordinates two molecules of zinc mediates the heterooligomerization with MDM2.PTM Phosphorylated. Phosphorylation at Ser-367 promotes interaction with YWHAG and subsequent ubiquitination and degradation. Phosphorylation at Ser-342 also induces ubiquitination and degradation but to a lower extent.PTM Ubiquitinated and degraded by MDM2. Deubiquitination by USP2 on the other hand stabilizes the MDM4 protein.SIMILARITY Belongs to the MDM2/MDM4 family. UniProt O15151 1 EQUAL 490 EQUAL Reactome Database ID Release 81 349430 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=349430 Reactome R-HSA-349430 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-349430.1 1 1 Reactome Database ID Release 81 6804932 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=6804932 Reactome R-HSA-6804932 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-6804932.1 p-S166,S188-MDM2:p-S403-MDM4 Reactome DB_ID: 6804939 p-S403-MDM4 phospho-Mdmx (Ser-403) Reactome DB_ID: 349461 403 EQUAL 1 EQUAL 490 EQUAL Reactome Database ID Release 81 349461 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=349461 Reactome R-HSA-349461 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-349461.1 1 1 Reactome Database ID Release 81 6804939 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=6804939 Reactome R-HSA-6804939 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-6804939.1 ACTIVATION Reactome Database ID Release 81 349455 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=349455 Reactome R-HSA-349455 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-349455.3 15788536 Pubmed 2005 Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage Pereg, Y Shkedy, D de Graaf, P Meulmeester, E Edelson-Averbukh, M Salek, M Biton, S Teunisse, AF Lehmann, Wolf Jochemsen, AG Shiloh, Y Proc Natl Acad Sci U S A 102:5056-61 16163388 Pubmed 2005 ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage Chen, L Gilkes, DM Pan, Y Lane, WS Chen, J EMBO J 24:3411-22 LEFT-TO-RIGHT 2.7.11.1 Phosphorylation of MDM4 by CHEK2 CHEK2 (Chk2) kinase is required for phosphorylation of MDM4 at serine residues S342 and S367 in vivo. CHEK2-mediated phosphorylation stimulates MDM4 ubiquitination by MDM2 and subsequent degradation (Chen et al. 2005). Authored: Matthews, L, 2008-03-31 10:45:58 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Matthews, L, 2008-05-12 14:39:01 2 p-S166,S188-MDM2:p-S346,S367,S403-MDM4 Reactome DB_ID: 6804936 p-S346,S367,S403-MDM4 Reactome DB_ID: 349441 342 EQUAL 367 EQUAL 1 EQUAL 490 EQUAL Reactome Database ID Release 81 349441 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=349441 Reactome R-HSA-349441 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-349441.1 1 1 Reactome Database ID Release 81 6804936 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=6804936 Reactome R-HSA-6804936 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-6804936.1 2 ACTIVATION Reactome Database ID Release 81 349426 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=349426 Reactome R-HSA-349426 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-349426.2 LEFT-TO-RIGHT MDM2 forms homo- or heterodimers To efficiently function as an E3 ubiquitin ligase, MDM2 has to form dimers or higher order oligomers. MDM2 can homodimerize (Cheng et al. 2011) or heterodimerize with MDM4 (MDMX) (Sharp et al. 1999, Huang et al. 2011, Pant et al. 2011). Dimerization involves the RING domain of MDM2 and/or MDM4. Heterodimers of MDM2 and MDM4 may be particularly important during embryonic development (Pant et al. 2011). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 Converted from EntitySet in Reactome p-S166,S188-MDM2,MDM4 Reactome DB_ID: 6804750 Reactome Database ID Release 81 6804750 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=6804750 Reactome R-HSA-6804750 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-6804750.1 2 Converted from EntitySet in Reactome p-S166,S188-MDM2 dimer, p-S166,S188-MDM2:MDM4 Reactome DB_ID: 6804745 p-S166,S188-MDM2 dimer Reactome DB_ID: 6804933 2 Reactome Database ID Release 81 6804933 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=6804933 Reactome R-HSA-6804933 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-6804933.1 Reactome Database ID Release 81 6804745 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=6804745 Reactome R-HSA-6804745 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-6804745.2 Reactome Database ID Release 81 6804741 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=6804741 Reactome R-HSA-6804741 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-6804741.4 21730163 Pubmed 2011 The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo Huang, Lei Yan, Zheng Liao, Xiaodong Li, Yuan Yang, Jie Wang, Zhu-Gang Zuo, Yong Kawai, Hidehiko Shadfan, Miriam Ganapathy, Suthakar Yuan, Zhi-Min Proc. Natl. Acad. Sci. U.S.A. 108:12001-6 10608892 Pubmed 1999 Stabilization of the MDM2 oncoprotein by interaction with the structurally related MDMX protein Sharp, D A Kratowicz, S A Sank, M J George, D L J. Biol. Chem. 274:38189-96 21730132 Pubmed 2011 Heterodimerization of Mdm2 and Mdm4 is critical for regulating p53 activity during embryogenesis but dispensable for p53 and Mdm2 stability Pant, Vinod Xiong, Shunbin Iwakuma, Tomoo Quintás-Cardama, Alfonso Lozano, Guillermina Proc. Natl. Acad. Sci. U.S.A. 108:11995-2000 INHIBITION Reactome Database ID Release 81 8979257 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=8979257 Reactome R-HSA-8979257 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-8979257.1 LEFT-TO-RIGHT MDM2 ubiquitinates phosphorylated MDM4 Once MDM4 is phosphorylated by ATM and CHEK2 in response to DNA damage, MDM2 ubiquitinates MDM4 and targets it for degradation (Chen et al. 2005, Pereg et al. 2005). The presence of MDM4 stimulates auto-ubiquitination of MDM2 (Linares et al. 2003). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 Converted from EntitySet in Reactome Ub Ubiquitin UBIQ_HUMAN Reactome DB_ID: 68524 RPS27A(1-76) ubiquitin (RPS27A) Reactome DB_ID: 939849 UniProt:P62979 RPS27A RPS27A UBA80 UBCEP1 SUBUNIT Ribosomal protein S27a is part of the 40S ribosomal subunit.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eS31 family. UniProt P62979 1 EQUAL 76 EQUAL Reactome Database ID Release 81 939849 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=939849 Reactome R-HSA-939849 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-939849.1 UBA52(1-76) ubiquitin (UBA52) Reactome DB_ID: 939844 UniProt:P62987 UBA52 UBA52 UBCEP2 SUBUNIT Ribosomal protein L40 is part of the 60S ribosomal subunit. Interacts with UBQLN1 (via UBA domain).MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eL40 family. UniProt P62987 1 EQUAL 76 EQUAL Reactome Database ID Release 81 939844 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=939844 Reactome R-HSA-939844 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-939844.1 UBB UBB(1-76) ubiquitin (UBB 1) Reactome DB_ID: 939847 UniProt:P0CG47 UBB UBB SUBUNIT Interacts with SKP1-KMD2A and SKP1-KMD2B complexes.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS The mRNA encoding variant UBB(+1) is produced by an unknown mechanism involving the deletion of a GT dinucleotide in the close proximity of a GAGAG motif (PubMed:9422699). This variant mRNA is found in normal brain, but the encoded protein accumulates only in brain neurofibrillary tangles and neuritic plaques in Alzheimer disease and other tauopathies, as well as polyglutaminopathies (PubMed:14597671). UBB(+1) variant cannot be used for polyubiquitination, is not effectively degraded by the proteasome when ubiquitinated and ubiquitinated UBB(+1) is refractory to disassembly by deubiquitinating enzymes (DUBs). In healthy brain, UBB(+1) C-terminus can be cleaved by UCHL3 (PubMed:21762696).MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY Belongs to the ubiquitin family. UniProt P0CG47 1 EQUAL 76 EQUAL Reactome Database ID Release 81 939847 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=939847 Reactome R-HSA-939847 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-939847.1 UBB(77-152) ubiquitin (UBB 2) Reactome DB_ID: 939870 77 EQUAL 152 EQUAL Reactome Database ID Release 81 939870 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=939870 Reactome R-HSA-939870 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-939870.1 UBB(153-228) ubiquitin (UBB 3) Reactome DB_ID: 939854 153 EQUAL 228 EQUAL Reactome Database ID Release 81 939854 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=939854 Reactome R-HSA-939854 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-939854.1 UBC UBC(1-76) ubiquitin (UBC 1) Reactome DB_ID: 939871 UniProt:P0CG48 UBC UBC MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For the sake of clarity sequence features are annotated only for the first chain, and are not repeated for each of the following chains.SIMILARITY Belongs to the ubiquitin family. UniProt P0CG48 1 EQUAL 76 EQUAL Reactome Database ID Release 81 939871 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=939871 Reactome R-HSA-939871 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-939871.1 UBC(77-152) ubiquitin (UBC 2) Reactome DB_ID: 939869 77 EQUAL 152 EQUAL Reactome Database ID Release 81 939869 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=939869 Reactome R-HSA-939869 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-939869.1 UBC(153-228) ubiquitin (UBC 3) Reactome DB_ID: 939853 153 EQUAL 228 EQUAL Reactome Database ID Release 81 939853 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=939853 Reactome R-HSA-939853 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-939853.1 UBC(229-304) ubiquitin (UBC 4) Reactome DB_ID: 939857 229 EQUAL 304 EQUAL Reactome Database ID Release 81 939857 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=939857 Reactome R-HSA-939857 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-939857.1 UBC(305-380) ubiquitin (UBC 5) Reactome DB_ID: 939863 305 EQUAL 380 EQUAL Reactome Database ID Release 81 939863 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=939863 Reactome R-HSA-939863 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-939863.1 UBC(381-456) ubiquitin (UBC 6) Reactome DB_ID: 939856 381 EQUAL 456 EQUAL Reactome Database ID Release 81 939856 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=939856 Reactome R-HSA-939856 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-939856.1 UBC(457-532) ubiquitin (UBC 7) Reactome DB_ID: 939862 457 EQUAL 532 EQUAL Reactome Database ID Release 81 939862 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=939862 Reactome R-HSA-939862 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-939862.1 UBC(533-608) ubiquitin (UBC 8) Reactome DB_ID: 939866 533 EQUAL 608 EQUAL Reactome Database ID Release 81 939866 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=939866 Reactome R-HSA-939866 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-939866.1 UBC(609-684) ubiquitin (UBC 9) Reactome DB_ID: 939868 609 EQUAL 684 EQUAL Reactome Database ID Release 81 939868 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=939868 Reactome R-HSA-939868 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-939868.1 Reactome Database ID Release 81 68524 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=68524 Reactome R-HSA-68524 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-68524.3 6 PolyUb,p-S166,S188-MDM2:PolyUb,p-S342,S367,S403-MDM4 Reactome DB_ID: 6804937 PolyUb,p-S342,S367,S403-MDM4 Reactome DB_ID: 6804938 ubiquitinylated lysine MOD MOD:01148 1 EQUAL 490 EQUAL Reactome Database ID Release 81 6804938 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=6804938 Reactome R-HSA-6804938 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-6804938.1 1 Ub,p-MDM2 PolyUb,p-S166,S188-MDM2 PolyUb,p-S166,188-MDM2 PolyUb,p-MDM2 Ub,p-S166,S188-MDM2 Ub,p-S166,188-MDM2 Reactome DB_ID: 6795669 1 EQUAL 491 EQUAL Reactome Database ID Release 81 6795669 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=6795669 Reactome R-HSA-6795669 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-6795669.1 1 Reactome Database ID Release 81 6804937 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=6804937 Reactome R-HSA-6804937 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-6804937.1 ACTIVATION GENE ONTOLOGY GO:0061630 Reactome Database ID Release 81 6804946 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=6804946 Reactome Database ID Release 81 6804724 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=6804724 Reactome R-HSA-6804724 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-6804724.1 14507994 Pubmed 2003 HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53 Linares, Laëtitia K Hengstermann, Arnd Ciechanover, Aaron Muller, Stefan Scheffner, Martin Proc. Natl. Acad. Sci. U.S.A. 100:12009-14 LEFT-TO-RIGHT MDM2 binds TP53 The N-terminal portion of MDM2 binds the N-terminal transactivation domain of TP53 (p53) and inhibits transcriptional transactivation by TP53 (Momand et al. 1992, Oliner et al. 1992, Oliner et al. 1993, Chen et al. 1993). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 p-S166,S188-MDM2 dimer, p-S166,S188-MDM2,MDM4:TP53 Reactome DB_ID: 6804885 1 1 Reactome Database ID Release 81 6804885 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=6804885 Reactome R-HSA-6804885 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-6804885.2 Reactome Database ID Release 81 5633460 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=5633460 Reactome R-HSA-5633460 6 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-5633460.6 8479525 Pubmed 1993 Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53 Oliner, J D Pietenpol, J A Thiagalingam, S Gyuris, J Kinzler, K W Vogelstein, B Nature 362:857-60 7686617 Pubmed 1993 Mapping of the p53 and mdm-2 interaction domains Chen, J Marechal, V Levine, A J Mol. Cell. Biol. 13:4107-14 1535557 Pubmed 1992 The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation Momand, J Zambetti, G P Olson, D C George, D Levine, A J Cell 69:1237-45 1614537 Pubmed 1992 Amplification of a gene encoding a p53-associated protein in human sarcomas Oliner, J D Kinzler, K W Meltzer, P S George, D L Vogelstein, B Nature 358:80-3 INHIBITION Reactome Database ID Release 81 8979263 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=8979263 Reactome R-HSA-8979263 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-8979263.1 NZF PHF20 PHD finger protein 20 Glioma-expressed antigen 2 Hepatocellular carcinoma-associated antigen 58 Novel zinc finger protein Transcription factor TZP C20orf104 GLEA2 HCA58 TZP Reactome DB_ID: 3222239 UniProt:Q9BVI0 PHF20 PHF20 C20orf104 GLEA2 HCA58 NZF TZP FUNCTION Methyllysine-binding protein, component of the MOF histone acetyltransferase protein complex. Not required for maintaining the global histone H4 'Lys-16' acetylation (H4K16ac) levels or locus specific histone acetylation, but instead works downstream in transcriptional regulation of MOF target genes (By similarity). As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. Contributes to methyllysine-dependent p53/TP53 stabilization and up-regulation after DNA damage.SUBUNIT Homodimer; disulfide-linked. Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, KAT8/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10. Component of the NSL complex at least composed of MOF/KAT8, KANSL1, KANSL2, KANSL3, MCRS1, PHF20, OGT1/OGT, WDR5 and HCFC1.TISSUE SPECIFICITY Expressed in heart, kidney, liver, lung, pancreas, placenta, spleen and testis. Not expressed in brain, skeletal muscle, colon, ovary, prostate, small intestine and thymus. Expressed in colon and ovary cancer cell lines while it is not expressed in the respective normal tissues.DOMAIN The Tudor domain 2 mediates reading of dimethyl-lysine residues.DOMAIN The Tudor domain 1 doesn't bind dimethyl-lysine residues, due to an atypical and occluded aromatic cage.MISCELLANEOUS Antibodies against PHF20 are present in sera from patients with hepatocellular carcinoma, glioblastoma and childhood medulloblastula. UniProt Q9BVI0 1 EQUAL 1012 EQUAL Reactome Database ID Release 81 3222239 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=3222239 Reactome R-HSA-3222239 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-3222239.1 LEFT-TO-RIGHT MDM2 ubiquitinates TP53 MDM2 is an ubiquitin ligase whose expression is positively regulated by TP53 (p53) (Wu et al. 1993). MDM2 binds TP53 tetramer (Maki 1999) and promotes its ubiquitination and subsequent degradation (Fuchs et al. 1998). Formation of MDM2 homodimers (Cheng et al. 2011) or heterodimers with MDM4 (MDMX) is needed for efficient ubiquitination of TP53 (Linares et al. 2003). While MDM2-TP53 binding occurs at the amino-terminus of TP53, MDM2 ubiquitinates TP53 lysine residues at the carboxy-terminus. Acetylation of those lysines can inhibit MDM2-dependent ubiquitination (Li et al. 2002). Authored: Orlic-Milacic, M, 2013-07-15 Reviewed: Samarajiwa, Shamith, 2013-09-03 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: D'Eustachio, P, 2013-07-15 Edited: Matthews, L, 2013-07-15 12 PolyUb-TP53 Tetramer Reactome DB_ID: 3209186 PolyUb-p53 PolyUb-TP53 Reactome DB_ID: 6793679 1 EQUAL 393 EQUAL Reactome Database ID Release 81 6793679 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=6793679 Reactome R-HSA-6793679 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-6793679.1 4 Reactome Database ID Release 81 3209186 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=3209186 Reactome R-HSA-3209186 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-3209186.2 ACTIVATION Reactome Database ID Release 81 6804883 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=6804883 Reactome Database ID Release 81 6804879 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=6804879 Reactome R-HSA-6804879 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-6804879.4 9824166 Pubmed 1998 Mdm2 association with p53 targets its ubiquitination Fuchs, S Y Adler, V Buschmann, T Wu, X Ronai, Z Oncogene 17:2543-7 10347217 Pubmed 1999 Oligomerization is required for p53 to be efficiently ubiquitinated by MDM2 Maki, C G J. Biol. Chem. 274:16531-5 8319905 Pubmed 1993 The p53-mdm-2 autoregulatory feedback loop Wu, X Bayle, J H Olson, D Levine, A J Genes Dev. 7:1126-32 10722742 Pubmed 2000 Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53 Fang, S Jensen, J P Ludwig, R L Vousden, K H Weissman, A M J. Biol. Chem. 275:8945-51 12421820 Pubmed 2002 Acetylation of p53 inhibits its ubiquitination by Mdm2 Li, Muyang Luo, Jianyuan Brooks, Christopher L Gu, Wei J. Biol. Chem. 277:50607-11 INHIBITION activeUnit: #Protein31 Reactome Database ID Release 81 8979105 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=8979105 Reactome R-HSA-8979105 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-8979105.1 p14ARF:p-S166,S188-MDM2 dimer,p-S166,S188-MDM2:MDM4 Reactome DB_ID: 6804995 1 p14ARF Cyclin-dependent kinase inhibitor 2A, isoform 4 p19ARF Reactome DB_ID: 1629813 UniProt:Q8N726 CDKN2A CDKN2A CDKN2 MLM FUNCTION Capable of inducing cell cycle arrest in G1 and G2 phases. Acts as a tumor suppressor. Binds to MDM2 and blocks its nucleocytoplasmic shuttling by sequestering it in the nucleolus. This inhibits the oncogenic action of MDM2 by blocking MDM2-induced degradation of p53 and enhancing p53-dependent transactivation and apoptosis. Also induces G2 arrest and apoptosis in a p53-independent manner by preventing the activation of cyclin B1/CDC2 complexes. Binds to BCL6 and down-regulates BCL6-induced transcriptional repression. Binds to E2F1 and MYC and blocks their transcriptional activator activity but has no effect on MYC transcriptional repression. Binds to TOP1/TOPOI and stimulates its activity. This complex binds to rRNA gene promoters and may play a role in rRNA transcription and/or maturation. Interacts with NPM1/B23 and promotes its polyubiquitination and degradation, thus inhibiting rRNA processing. Interacts with COMMD1 and promotes its 'Lys63'-linked polyubiquitination. Interacts with UBE2I/UBC9 and enhances sumoylation of a number of its binding partners including MDM2 and E2F1. Binds to HUWE1 and represses its ubiquitin ligase activity. May play a role in controlling cell proliferation and apoptosis during mammary gland development. Isoform smARF may be involved in regulation of autophagy and caspase-independent cell death; the short-lived mitochondrial isoform is stabilized by C1QBP.SUBUNIT Does not interact with cyclins, CDK1, CDK2, CDK4, CDK5 or CDK6. Binds to BCL6, E2F1, HUWE1, MDM2, MYC, NPM1/B23, TOP1/TOPOI and UBE2I/UBC9. Interacts with TBRG1 and COMMD1. Interacts with CDKN2AIP and E4F1. Interacts with CDK5RAP3 and MDM2; form a ternary complex involved in regulation of p53/TP53 (PubMed:16173922). Isoform smARF interacts with C1QBP. Interacts with NOP53; the interaction is direct and promotes ARF nucleoplasmic relocalization and ubiquitin-mediated proteasomal degradation (PubMed:27323397).PTM Ubiquitinated in normal cells by TRIP12 via the ubiquitin fusion degradation (UFD) pathway, a process that mediates ubiquitination at the N-terminus, regardless of the absence of lysine residues. Ubiquitination leads to its proteasomal degradation. In cancer cells, however, TRIP12 is located in a different cell compartment, preventing ubiquitination and degradation.CAUTION The proteins described here are encoded by the gene CDKN2A, but are completely unrelated in terms of sequence and function to cyclin-dependent kinase inhibitor 2A (AC P42771) which is encoded by the same gene. UniProt Q8N726 1 EQUAL 132 EQUAL Reactome Database ID Release 81 1629813 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=1629813 Reactome R-HSA-1629813 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-1629813.2 1 Reactome Database ID Release 81 6804995 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=6804995 Reactome R-HSA-6804995 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-6804995.3 LEFT-TO-RIGHT Ubiquitinated TP53 translocates to the cytosol Upon MDM2-mediated ubiquitination, TP53 is exported from the nucleus to the cytosol. TP53 nuclear export requires the nuclear export sequence (NES) of TP53, but not the NES of MDM2 (Boyd et al. 2000. Geyer et al. 2000). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 PolyUb-TP53 Tetramer Reactome DB_ID: 8856287 cytosol GENE ONTOLOGY GO:0005829 PolyUb-p53 PolyUb-TP53 Reactome DB_ID: 6793681 1 EQUAL 393 EQUAL Reactome Database ID Release 81 6793681 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=6793681 Reactome R-HSA-6793681 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-6793681.1 4 Reactome Database ID Release 81 8856287 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=8856287 Reactome R-HSA-8856287 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-8856287.1 Reactome Database ID Release 81 6793685 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=6793685 Reactome R-HSA-6793685 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-6793685.2 10980695 Pubmed 2000 An intact HDM2 RING-finger domain is required for nuclear exclusion of p53 Boyd, S D Tsai, K Y Jacks, T Nat. Cell Biol. 2:563-8 10980696 Pubmed 2000 The MDM2 RING-finger domain is required to promote p53 nuclear export Geyer, R K Yu, Z K Maki, C G Nat. Cell Biol. 2:569-73 Autodegradation of the E3 ubiquitin ligase COP1 COP1 is one of several E3 ubiquitin ligases responsible for the tight regulation of p53 abundance. Following DNA damage, COP1 dissociates from p53 and is inactivated by autodegradation via a pathway involving ATM phosphorylation of COP1 on Ser(387), autoubiquitination and proteasome mediated degradation. Destruction of COP1 results in abrogation of the ubiquitination and degradation of p53 (Dornan et al., 2006). Authored: Matthews, L, 2008-06-12 21:09:06 Reviewed: Dixit, VM, 2009-11-17 Edited: Matthews, L, 2009-11-09 LEFT-TO-RIGHT 2.7.11.1 Phosphorylation of COP1 at Ser-387 by ATM ATM phosphorylates COP1 on Ser387 in response to DNA damage (Dornan et al., 2006). Authored: Matthews, L, 2008-06-12 21:09:06 Reviewed: Dixit, VM, 2009-11-17 Edited: Matthews, L, 2009-10-21 COP1 RFWD2 Reactome DB_ID: 349454 UniProt:Q8NHY2 COP1 COP1 RFWD2 RNF200 FUNCTION E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Involved in JUN ubiquitination and degradation. Directly involved in p53 (TP53) ubiquitination and degradation, thereby abolishing p53-dependent transcription and apoptosis. Ubiquitinates p53 independently of MDM2 or RCHY1. Probably mediates E3 ubiquitin ligase activity by functioning as the essential RING domain subunit of larger E3 complexes. In contrast, it does not constitute the catalytic RING subunit in the DCX DET1-COP1 complex that negatively regulates JUN, the ubiquitin ligase activity being mediated by RBX1. Involved in 14-3-3 protein sigma/SFN ubiquitination and proteasomal degradation, leading to AKT activation and promotion of cell survival. Ubiquitinates MTA1 leading to its proteasomal degradation. Upon binding to TRIB1, ubiquitinates CEBPA, which lacks a canonical COP1-binding motif (Probable).ACTIVITY REGULATION TRIB1 competes with substrates for RFWD2 binding.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homodimer. Homodimerization is mediated by the coiled coil domain. Component of the DCX DET1-COP1 ubiquitin ligase complex at least composed of RBX1, DET1, DDB1, CUL4A and COP1. Isoform 2 does not interact with CUL4A but still binds to RBX1, suggesting that the interaction may be mediated by another cullin protein. Isoform 1 and isoform 2 interact with CUL5 but not with CUL1, CUL2 not CUL3. Interacts with bZIP transcription factors JUN, JUNB and JUND but not with FOS, ATF2 nor XBP1. Interacts with p53 (TP53). Interacts with COPS6; this interaction stabilizes RFWD2 through reducing its auto-ubiquitination and decelerating its turnover rate. Interacts with SFN; this interaction leads to SFN degradation. Isoform 4 forms heterodimers with isoform 1, preventing its association with DET1. Interacts with p53/TP53 and MTA1. Interacts with TRIB1 (via C-terminus) and TRIB2 (PubMed:20410507, PubMed:27041596).TISSUE SPECIFICITY Ubiquitously expressed at low level. Expressed at higher level in testis, placenta, skeletal muscle and heart.INDUCTION By p53/TP53.DOMAIN The RING finger domain, in addition to its role in ubiquitination, functions as a structural scaffold to bring two clusters of positive-charged residues within spatial proximity to mimic a bipartite nuclear localization signal (NLS) (By similarity).DOMAIN The WD40 domain (386-731) is necessary and sufficient for TRIB1 binding (PubMed:27041596).PTM Autoubiquitinated. MTA1 destabilizes it by promoting its autoubiquitination.SIMILARITY Belongs to the COP1 family. UniProt Q8NHY2 1 EQUAL 731 EQUAL Reactome Database ID Release 81 349454 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=349454 Reactome R-HSA-349454 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-349454.1 p-S387-RFWD2 phospho-COP1(Ser 387) Reactome DB_ID: 349450 387 EQUAL 1 EQUAL 731 EQUAL Reactome Database ID Release 81 349450 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=349450 Reactome R-HSA-349450 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-349450.1 ACTIVATION Reactome Database ID Release 81 349444 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=349444 Reactome R-HSA-349444 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-349444.4 16931761 Pubmed 2006 ATM engages autodegradation of the E3 ubiquitin ligase COP1 after DNA damage Dornan, D Shimizu, H Mah, A Dudhela, T Eby, M O'Rourke, K Seshagiri, S Dixit, VM Science 313:1122-6 LEFT-TO-RIGHT Dissociation of the COP1-p53 complex ATM-dependent phosphorylation of COP1 on Ser(387) results in disruption of the COP1-p53 complex (Dornan et al., 2006) Authored: Matthews, L, 2008-06-12 21:09:06 Reviewed: Dixit, VM, 2009-11-17 Edited: Matthews, L, 2009-11-09 p-S387-RFWD2:p-S15-TP53 Phospho-COP1(Ser-387):p53 complex Reactome DB_ID: 349420 1 1 Reactome Database ID Release 81 349420 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=349420 Reactome R-HSA-349420 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-349420.1 Reactome Database ID Release 81 264435 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=264435 Reactome R-HSA-264435 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-264435.2 LEFT-TO-RIGHT Translocation of COP1 from the nucleus to the cytoplasm Ionizing radiation results in an ATM-dependent movement of COP1 from the nucleus to the cytoplasm (Dornan et al., 2006). Authored: Matthews, L, 2008-06-12 21:09:06 Reviewed: Dixit, VM, 2009-11-17 Edited: Matthews, L, 2009-11-09 p-S387-RFWD2 phosho-COP1(ser-387) Reactome DB_ID: 349439 1 EQUAL 731 EQUAL Reactome Database ID Release 81 349439 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=349439 Reactome R-HSA-349439 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-349439.1 Reactome Database ID Release 81 264418 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=264418 Reactome R-HSA-264418 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-264418.3 LEFT-TO-RIGHT 6.3.2.19 Autoubiquitination of phospho-COP1(Ser-387 ) ATM phosphorylation promotes autoubiquitination of COP1 in vitro (Dornan et al., 2006). The number of ubiquitin molecules shown in this reaction is set arbitrarily at 4. Authored: Matthews, L, 2008-06-12 21:09:06 Reviewed: Dixit, VM, 2009-11-17 Edited: Matthews, L, 2008-04-30 12:41:30 Converted from EntitySet in Reactome Ub ubiquitin Reactome DB_ID: 113595 RPS27A RPS27A(1-76) ubiquitin (RPS27A) Reactome DB_ID: 939205 1 EQUAL 76 EQUAL Reactome Database ID Release 81 939205 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=939205 Reactome R-HSA-939205 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-939205.1 UBA52 UBA52(1-76) ubiquitin (UBA52) Reactome DB_ID: 939203 1 EQUAL 76 EQUAL Reactome Database ID Release 81 939203 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=939203 Reactome R-HSA-939203 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-939203.1 UBB UBB(1-76) ubiquitin (UBB 1) Reactome DB_ID: 939214 1 EQUAL 76 EQUAL Reactome Database ID Release 81 939214 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=939214 Reactome R-HSA-939214 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-939214.1 UBB(77-152) ubiquitin (UBB 2) Reactome DB_ID: 939213 77 EQUAL 152 EQUAL Reactome Database ID Release 81 939213 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=939213 Reactome R-HSA-939213 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-939213.1 UBB(153-228) ubiquitin (UBB 3) Reactome DB_ID: 939230 153 EQUAL 228 EQUAL Reactome Database ID Release 81 939230 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=939230 Reactome R-HSA-939230 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-939230.1 UBC UBC(1-76) ubiquitin (UBC 1) Reactome DB_ID: 939188 1 EQUAL 76 EQUAL Reactome Database ID Release 81 939188 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=939188 Reactome R-HSA-939188 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-939188.1 UBC(77-152) ubiquitin (UBC 2) Reactome DB_ID: 939164 77 EQUAL 152 EQUAL Reactome Database ID Release 81 939164 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=939164 Reactome R-HSA-939164 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-939164.1 UBC(153-228) ubiquitin (UBC 3) Reactome DB_ID: 939258 153 EQUAL 228 EQUAL Reactome Database ID Release 81 939258 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=939258 Reactome R-HSA-939258 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-939258.1 UBC(229-304) ubiquitin (UBC 4) Reactome DB_ID: 939192 229 EQUAL 304 EQUAL Reactome Database ID Release 81 939192 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=939192 Reactome R-HSA-939192 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-939192.1 UBC(305-380) ubiquitin (UBC 5) Reactome DB_ID: 939232 305 EQUAL 380 EQUAL Reactome Database ID Release 81 939232 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=939232 Reactome R-HSA-939232 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-939232.1 UBC(381-456) ubiquitin (UBC 6) Reactome DB_ID: 939191 381 EQUAL 456 EQUAL Reactome Database ID Release 81 939191 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=939191 Reactome R-HSA-939191 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-939191.1 UBC(457-532) ubiquitin (UBC 7) Reactome DB_ID: 939184 457 EQUAL 532 EQUAL Reactome Database ID Release 81 939184 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=939184 Reactome R-HSA-939184 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-939184.1 UBC(533-608) ubiquitin (UBC 8) Reactome DB_ID: 939239 533 EQUAL 608 EQUAL Reactome Database ID Release 81 939239 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=939239 Reactome R-HSA-939239 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-939239.1 UBC(609-684) ubiquitin (UBC 9) Reactome DB_ID: 939165 609 EQUAL 684 EQUAL Reactome Database ID Release 81 939165 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=939165 Reactome R-HSA-939165 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-939165.1 Reactome Database ID Release 81 113595 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=113595 Reactome R-HSA-113595 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-113595.1 4 ubiquitinated phospho-COP1(ser-387) Reactome DB_ID: 349433 4 1 Reactome Database ID Release 81 349433 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=349433 Reactome R-HSA-349433 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-349433.1 ACTIVATION GENE ONTOLOGY GO:0004842 Reactome Database ID Release 81 349467 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=349467 Reactome Database ID Release 81 264444 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=264444 Reactome R-HSA-264444 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-264444.4 LEFT-TO-RIGHT Proteasome mediated degradation of COP1 Autoubiquitinated COP1 is degraded by the proteasome. The number of ubiquitin molecules shown in this reaction is arbitrarily set at 4. (Dornan et al., 2006). Authored: Matthews, L, 2008-06-12 21:09:06 Reviewed: Dixit, VM, 2009-11-17 Edited: Matthews, L, 2009-11-09 4 ACTIVATION 26S proteasome Reactome DB_ID: 68819 PSMA1 Proteasome subunit alpha type 1 Proteasome component C2 Macropain subunit C2 Multicatalytic endopeptidase complex subunit C2 Proteasome nu chain 30 kDa prosomal protein PROS-30 Reactome DB_ID: 68724 UniProt:P25786 PSMA1 PSMA1 HC2 NU PROS30 PSC2 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with NOTCH3. Interacts with ZFAND1 (PubMed:29804830).INDUCTION Induced in breast cancer tissue (at protein level). Up-regulated in liver tumor tissues.SIMILARITY Belongs to the peptidase T1A family. UniProt P25786 1 EQUAL 263 EQUAL Reactome Database ID Release 81 68724 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=68724 Reactome R-HSA-68724 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-68724.2 1 PSMD11 26S proteasome non-ATPase regulatory subunit 11 26S proteasome regulatory subunit S9 26S proteasome regulatory subunit p44.5 Reactome DB_ID: 68790 UniProt:O00231 PSMD11 PSMD11 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. In the complex, PSMD11 is required for proteasome assembly. Plays a key role in increased proteasome activity in embryonic stem cells (ESCs): its high expression in ESCs promotes enhanced assembly of the 26S proteasome, followed by higher proteasome activity.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD11, a base containing 6 ATPases and few additional components.TISSUE SPECIFICITY Highly expressed in embryonic stem cells (ESCs). Expression decreases as ESCs differentiate.INDUCTION By FOXO4; expression in embryonic stem cells (ESCs) is mediated by FOXO4.PTM Phosphorylated by AMPK.SIMILARITY Belongs to the proteasome subunit S9 family. UniProt O00231 2 EQUAL 422 EQUAL Reactome Database ID Release 81 68790 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=68790 Reactome R-HSA-68790 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-68790.2 1 PSME3 Proteasome activator complex subunit 3 Proteasome activator 28-gamma subunit PA28gamma PA28g Activator of multicatalytic protease subunit 3 11S regulator complex gamma subunit REG-gamma Ki nuclear autoantigen Reactome DB_ID: 68816 UniProt:P61289 PSME3 PSME3 FUNCTION Subunit of the 11S REG-gamma (also called PA28-gamma) proteasome regulator, a doughnut-shaped homoheptamer which associates with the proteasome. 11S REG-gamma activates the trypsin-like catalytic subunit of the proteasome but inhibits the chymotrypsin-like and postglutamyl-preferring (PGPH) subunits. Facilitates the MDM2-p53/TP53 interaction which promotes ubiquitination- and MDM2-dependent proteasomal degradation of p53/TP53, limiting its accumulation and resulting in inhibited apoptosis after DNA damage. May also be involved in cell cycle regulation. Mediates CCAR2 and CHEK2-dependent SIRT1 inhibition (PubMed:25361978).SUBUNIT Homoheptamer; the stability of the heptamer is essential for the specific activation of the trypsine-like subunit and inhibition of the chymotrypsin-like and postglutamyl-preferring (PGPH) subunits of the proteasome. Interacts with p53/TP53 and MDM2. Interacts with MAP3K3 (By similarity). Associates with the proteasome. Interacts with CCAR2. Interacts with PSME3IP1 (via C-terminus); the interaction is direct and promotes the association of PSME3 with the 20S proteasome (PubMed:29934401). Interacts with COIL; the interaction is inhibited by PSME3IP1 (PubMed:29934401).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus UL27.INDUCTION Up-regulated in thyroid carcinoma cells.DOMAIN The C-terminal sequences affect heptamer stability and proteasome affinity.PTM Phosphorylated by MAP3K3 (By similarity). Phosphorylation at Ser-247 promotes its association with CCAR2.PTM Acetylation at the major site Lys-195 is important for oligomerization and ability to degrade its target substrates. Deacetylated by SIRT1.SIMILARITY Belongs to the PA28 family. UniProt P61289 2 EQUAL 254 EQUAL Reactome Database ID Release 81 68816 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=68816 Reactome R-HSA-68816 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-68816.2 1 PSMB2 Proteasome subunit beta type 2 Proteasome component C7-I Macropain subunit C7-I Multicatalytic endopeptidase complex subunit C7-I Reactome DB_ID: 68744 UniProt:P49721 PSMB2 PSMB2 FUNCTION Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.INDUCTION Up-regulated in ovarian cancer cell lines.SIMILARITY Belongs to the peptidase T1B family. UniProt P49721 1 EQUAL 201 EQUAL Reactome Database ID Release 81 68744 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=68744 Reactome R-HSA-68744 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-68744.2 1 PSMB8 Proteasome subunit beta type 8 Proteasome subunit beta type 8 precursor Proteasome component C13 Macropain subunit C13 Multicatalytic endopeptidase complex subunit C13 Reactome DB_ID: 68762 UniProt:P28062 PSMB8 PSMB8 LMP7 PSMB5i RING10 Y2 FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Replacement of PSMB5 by PSMB8 increases the capacity of the immunoproteasome to cleave model peptides after hydrophobic and basic residues. Involved in the generation of spliced peptides resulting from the ligation of two separate proteasomal cleavage products that are not contiguous in the parental protein (PubMed:27049119). Acts as a major component of interferon gamma-induced sensitivity. Plays a key role in apoptosis via the degradation of the apoptotic inhibitor MCL1. May be involved in the inflammatory response pathway. In cancer cells, substitution of isoform 1 (E2) by isoform 2 (E1) results in immunoproteasome deficiency. Required for the differentiation of preadipocytes into adipocytes.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB5. Component of the spermatoproteasome, a form of the proteasome specifically found in testis. Directly interacts with POMP. Interacts with TAP1.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.DEVELOPMENTAL STAGE Highly expressed in immature dendritic cells (at protein level).INDUCTION Up-regulated by IFNG/IFN-gamma and IRF1 (at protein level). Up-regulated by TNF (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Down-regulated by the selective inhibitor PR-957. Down-regulated in mature dendritic cells by HSV-1 infection. Up-regulated by heat shock treatment.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.SIMILARITY Belongs to the peptidase T1B family. UniProt P28062 73 EQUAL 276 EQUAL Reactome Database ID Release 81 68762 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=68762 Reactome R-HSA-68762 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-68762.2 1 PSMD10 26S proteasome non-ATPase regulatory subunit 10 26S proteasome regulatory subunit p28 Gankyrin Reactome DB_ID: 68788 UniProt:O75832 PSMD10 PSMD10 FUNCTION Acts as a chaperone during the assembly of the 26S proteasome, specifically of the PA700/19S regulatory complex (RC). In the initial step of the base subcomplex assembly is part of an intermediate PSMD10:PSMC4:PSMC5:PAAF1 module which probably assembles with a PSMD5:PSMC2:PSMC1:PSMD2 module. Independently of the proteasome, regulates EGF-induced AKT activation through inhibition of the RHOA/ROCK/PTEN pathway, leading to prolonged AKT activation. Plays an important role in RAS-induced tumorigenesis.FUNCTION Acts as an proto-oncoprotein by being involved in negative regulation of tumor suppressors RB1 and p53/TP53. Overexpression is leading to phosphorylation of RB1 and proteasomal degradation of RB1. Regulates CDK4-mediated phosphorylation of RB1 by competing with CDKN2A for binding with CDK4. Facilitates binding of MDM2 to p53/TP53 and the mono- and polyubiquitination of p53/TP53 by MDM2 suggesting a function in targeting the TP53:MDM2 complex to the 26S proteasome. Involved in p53-independent apoptosis. Involved in regulation of NF-kappa-B by retaining it in the cytoplasm. Binds to the NF-kappa-B component RELA and accelerates its XPO1/CRM1-mediated nuclear export.SUBUNIT Part of transient complex containing PSMD10, PSMC4, PSMC5 and PAAF1 formed during the assembly of the 26S proteasome. Stays associated throughout the assembly of the PA700/19S RC and is released upon association with the 20S core. Interacts with PSMC4. Interacts with RB1. Interacts with CDK4. Interacts with MDM2. Interacts with RELA. Associates with a CDK4:CCND2 serine/threonine kinase complex. Interacts with ARHGDIA and increases the interaction between ARHGDIA and RHOA, hence promotes ARHGDIA inactivation of RHOA and ROCK.TISSUE SPECIFICITY Tends to be up-regulated in cancer cells with RAS mutations, including lung cancers and adenocarconimas (at protein level).CAUTION Was initially identified as a genuine component of the 26S proteasome. UniProt O75832 1 EQUAL 226 EQUAL Reactome Database ID Release 81 68788 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=68788 Reactome R-HSA-68788 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-68788.2 1 AF PSMD4 26S proteasome non-ATPase regulatory subunit 4 26S proteasome regulatory subunit S5A Rpn10 Multiubiquitin chain binding protein Antisecretory factor-1 ASF Reactome DB_ID: 68800 UniProt:P55036 PSMD4 PSMD4 MCB1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMD4 acts as an ubiquitin receptor subunit through ubiquitin-interacting motifs and selects ubiquitin-conjugates for destruction. Displays a preferred selectivity for longer polyubiquitin chains.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD4 (PubMed:27428775, PubMed:27342858). Interacts with NUB1 (PubMed:11585840). Interacts with SQSTM1 (PubMed:15340068). Interacts with UBQLN4 (PubMed:15280365). Interacts with UBE3A (PubMed:22645313). Interacts with UBQLN1 (via ubiquitin-like domain) (PubMed:15147878). Interacts with DDI2 (PubMed:29290612).DOMAIN The 2 UIM motifs are involved in the binding to a multi-ubiquitin chain in a cooperative way.SIMILARITY Belongs to the proteasome subunit S5A family. UniProt P55036 1 EQUAL 377 EQUAL Reactome Database ID Release 81 68800 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=68800 Reactome R-HSA-68800 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-68800.2 1 PSMD5 26S proteasome non-ATPase regulatory subunit 5 26S proteasome subunit S5B 26S protease subunit S5 basic Reactome DB_ID: 68802 UniProt:Q16401 PSMD5 PSMD5 KIAA0072 FUNCTION Acts as a chaperone during the assembly of the 26S proteasome, specifically of the base subcomplex of the PA700/19S regulatory complex (RC). In the initial step of the base subcomplex assembly is part of an intermediate PSMD5:PSMC2:PSMC1:PSMD2 module which probably assembles with a PSMD10:PSMC4:PSMC5:PAAF1 module followed by dissociation of PSMD5.SUBUNIT Interacts with PSMC1, PSMC2, PSMD1 and PSMD6. Part of transient complex containing PSMD5, PSMC2, PSMC1 and PSMD2 formed during the assembly of the 26S proteasome.DOMAIN Rich in dileucine repeats, which have been implicated in trafficking of a variety of transmembrane proteins.SIMILARITY Belongs to the proteasome subunit S5B/HSM3 family.CAUTION Was initially identified as a genuine component of the 26S proteasome. UniProt Q16401 2 EQUAL 504 EQUAL Reactome Database ID Release 81 68802 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=68802 Reactome R-HSA-68802 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-68802.2 1 PSMA5 Proteasome subunit alpha type 5 Proteasome zeta chain Macropain zeta chain Multicatalytic endopeptidase complex zeta chain Reactome DB_ID: 68732 UniProt:P28066 PSMA5 PSMA5 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. PSMA5 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly.TISSUE SPECIFICITY Expressed in fetal brain (at protein level).INDUCTION Up-regulated in colon cancer cell lines. Up-regulated in fetal Down syndrome (DS) brain (at protein level). May be the target of the transcriptional activator NFE2L2.SIMILARITY Belongs to the peptidase T1A family. UniProt P28066 1 EQUAL 241 EQUAL Reactome Database ID Release 81 68732 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=68732 Reactome R-HSA-68732 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-68732.2 1 HSN3 PSMB4 Proteasome subunit beta type 4 Proteasome subunit beta type 4 precursor Proteasome beta chain Macropain beta chain Multicatalytic endopeptidase complex beta chain Proteasome chain 3 HsBPROS26 Reactome DB_ID: 68750 UniProt:P28070 PSMB4 PSMB4 PROS26 FUNCTION Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Forms a ternary complex with SMAD1 and OAZ1 before PSMB4 is incorporated into the 20S proteasome. Interacts with PRPF19 (PubMed:11571290, PubMed:12097147).SUBUNIT (Microbial infection) Interacts with HTLV-1 Tax protein.SUBUNIT (Microbial infection) Interacts with HIV-1 Nef and Tat proteins.INDUCTION Up-regulated in fibrolamellar carcinomas.SIMILARITY Belongs to the peptidase T1B family.CAUTION A report observed N-glycosylation at Asn-83 (PubMed:19139490). However, as the protein does not localize in an extracellular compartment of the cell, additional evidence is required to confirm this result. UniProt P28070 46 EQUAL 264 EQUAL Reactome Database ID Release 81 68750 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=68750 Reactome R-HSA-68750 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-68750.2 1 PSME1 Proteasome activator complex subunit 1 Proteasome activator 28-alpha subunit PA28alpha PA28a Activator of multicatalytic protease subunit 1 11S regulator complex alpha subunit REG-alpha Interferon gamma up-regulated I-5111 protein IGUP I-5111 Reactome DB_ID: 68812 UniProt:Q06323 PSME1 PSME1 IFI5111 FUNCTION Implicated in immunoproteasome assembly and required for efficient antigen processing. The PA28 activator complex enhances the generation of class I binding peptides by altering the cleavage pattern of the proteasome.SUBUNIT Heterodimer of PSME1 and PSME2, which forms a hexameric ring. PSME1 can form homoheptamers.INDUCTION By IFNG/IFN-gamma.SIMILARITY Belongs to the PA28 family. UniProt Q06323 1 EQUAL 249 EQUAL Reactome Database ID Release 81 68812 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=68812 Reactome R-HSA-68812 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-68812.2 1 PSMA3 Proteasome subunit alpha type 3 Proteasome component C8 Macropain subunit C8 Multicatalytic endopeptidase complex subunit C8 Reactome DB_ID: 68728 UniProt:P25788 PSMA3 PSMA3 HC8 PSC8 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Binds to the C-terminus of CDKN1A and thereby mediates its degradation. Negatively regulates the membrane trafficking of the cell-surface thromboxane A2 receptor (TBXA2R) isoform 2.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with AURKB. Interacts with CDKN1A (PubMed:11350925). Interacts with MDM2 and RB1 (PubMed:16337594). Interacts with the C-terminus of TBXA2R isoform 2 (PubMed:17499743). Interacts with DNAJB2 (PubMed:15936278).SUBUNIT (Microbial infection) Interacts with HIV-1 Tat protein.SUBUNIT (Microbial infection) Interacts with hepatitis C virus (HCV) F protein.SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus EBNA3 proteins.INDUCTION Down-regulated by antioxidants BO-653 and probucol. Up-regulated by bacterial lipopolysaccharides (LPS) and TNF.SIMILARITY Belongs to the peptidase T1A family. UniProt P25788 2 EQUAL 255 EQUAL Reactome Database ID Release 81 68728 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=68728 Reactome R-HSA-68728 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-68728.2 1 PSMB7 Proteasome subunit beta type 7 Proteasome subunit beta type 7 precursor Proteasome subunit Z Macropain chain Z Multicatalytic endopeptidase complex chain Z Reactome DB_ID: 68759 UniProt:Q99436 PSMB7 PSMB7 Z FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB7 displays a trypsin-like activity.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 Tat protein.TISSUE SPECIFICITY Expressed at a low level in colonic mucosa. Up-regulated in colorectal cancer tissues.SIMILARITY Belongs to the peptidase T1B family. UniProt Q99436 44 EQUAL 277 EQUAL Reactome Database ID Release 81 68759 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=68759 Reactome R-HSA-68759 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-68759.2 1 PSMB5 Proteasome subunit beta type 5 Proteasome subunit beta type 5 precursor Proteasome epsilon chain Macropain epsilon chain Multicatalytic endopeptidase complex epsilon chain Proteasome subunit X Proteasome chain 6 Proteasome subunit MB1 Reactome DB_ID: 68753 UniProt:P28074 PSMB5 PSMB5 LMPX MB1 X FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB5 displays a chymotrypsin-like activity.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Directly interacts with POMP (PubMed:15944226). Interacts with ABCB1 and TAP1 (PubMed:15488952).SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.INDUCTION Down-regulated by IFNG/IFN-gamma (at protein level). Induced in breast cancer tissue. Up-regulated by sulforaphane in breast cancer cells.SIMILARITY Belongs to the peptidase T1B family. UniProt P28074 60 EQUAL 263 EQUAL Reactome Database ID Release 81 68753 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=68753 Reactome R-HSA-68753 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-68753.2 1 SEM1 DSS1 SHFM1 26S proteasome complex subunit DSS1 DSS1_HUMAN Reactome DB_ID: 8866674 UniProt:P60896 SEM1 SEM1 DSS1 SHFDG1 SHFM1 C7orf76 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair (PubMed:15117943). Component of the TREX-2 complex (transcription and export complex 2), composed of at least ENY2, GANP, PCID2, SEM1, and either centrin CETN2 or CETN3 (PubMed:22307388). The TREX-2 complex functions in docking export-competent ribonucleoprotein particles (mRNPs) to the nuclear entrance of the nuclear pore complex (nuclear basket). TREX-2 participates in mRNA export and accurate chromatin positioning in the nucleus by tethering genes to the nuclear periphery. Binds and stabilizes BRCA2 and is thus involved in the control of R-loop-associated DNA damage and thus transcription-associated genomic instability. R-loop accumulation increases in SEM1-depleted cells.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including SEM1, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Belongs to the TREX-2 complex (transcription and export complex 2), composed of at least ENY2, GANP, PCID2, SEM1, and either centrin CETN2 or CETN3 (PubMed:22307388). Component of the homologous recombination repair (HR) complex composed of ERCC5/XPG, BRCA2, PALB2, DSS1 and RAD51 (PubMed:26833090). Interacts with the C-terminal of BRCA2 (PubMed:10373512, PubMed:21719596).TISSUE SPECIFICITY Expressed in limb bud, craniofacial primordia and skin.SIMILARITY Belongs to the DSS1/SEM1 family. UniProt P60896 1 EQUAL 70 EQUAL Reactome Database ID Release 81 8866674 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=8866674 Reactome R-HSA-8866674 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-8866674.3 1 PSMD13 26S proteasome non-ATPase regulatory subunit 13 26S proteasome regulatory subunit S11 26S proteasome regulatory subunit p40.5 Reactome DB_ID: 68794 UniProt:Q9UNM6 PSMD13 PSMD13 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD13, a base containing 6 ATPases and few additional components.SIMILARITY Belongs to the proteasome subunit S11 family. UniProt Q9UNM6 1 EQUAL 376 EQUAL Reactome Database ID Release 81 68794 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=68794 Reactome R-HSA-68794 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-68794.2 1 PSMD7 26S proteasome non-ATPase regulatory subunit 7 26S proteasome regulatory subunit S12 Proteasome subunit p40 Mov34 protein homolog Reactome DB_ID: 68806 UniProt:P51665 PSMD7 PSMD7 MOV34L FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD7, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Within the complex, PSMD7 interacts with subunit PSMD4 through their respective MPN domain. Interacts with TRIM5 (PubMed:22078707).MISCELLANEOUS Does not bind a metal ion.SIMILARITY Belongs to the peptidase M67A family. UniProt P51665 1 EQUAL 324 EQUAL Reactome Database ID Release 81 68806 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=68806 Reactome R-HSA-68806 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-68806.2 1 PSMD12 26S proteasome non-ATPase regulatory subunit 12 26S proteasome regulatory subunit p55 Reactome DB_ID: 68792 UniProt:O00232 PSMD12 PSMD12 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex (PubMed:27428775,PubMed:27342858). The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP) (PubMed:27428775,PubMed:27342858). The regulatory particle is made of a lid composed of 9 subunits including PSMD12, a base containing 6 ATPases and few additional components (PubMed:27428775,PubMed:27342858). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the proteasome subunit p55 family. UniProt O00232 2 EQUAL 456 EQUAL Reactome Database ID Release 81 68792 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=68792 Reactome R-HSA-68792 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-68792.2 1 PSMA4 Proteasome subunit alpha type 4 Proteasome component C9 Macropain subunit C9 Multicatalytic endopeptidase complex subunit C9 Proteasome subunit L Reactome DB_ID: 68730 UniProt:P25789 PSMA4 PSMA4 HC9 PSC9 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interaction with HTLV-1 TAX protein favors NFKB1 activation.INDUCTION Down-regulated by antioxidants BO-653 and probucol.SIMILARITY Belongs to the peptidase T1A family. UniProt P25789 1 EQUAL 261 EQUAL Reactome Database ID Release 81 68730 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=68730 Reactome R-HSA-68730 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-68730.2 1 PSMC5 Probable 26S protease regulatory subunit 8 Reactome DB_ID: 68780 UniProt:P62195 PSMC5 PSMC5 SUG1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC5 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC5 and few additional components (PubMed:27428775, PubMed:27342858). Component of a complex with USP49 and RUVBL1 (PubMed:23824326). Interacts with PRPF19. Interacts with TRIM5 (PubMed:22078707). Interacts with NDC80 (PubMed:9295362, PubMed:10409732). Interacts with PAAF1 (PubMed:15831487). Interacts, in vitro, with the thyroid hormone receptor (in a thyroid hormone T3-dependent manner) and with retinoid X receptor (RXR) (By similarity). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the AAA ATPase family. UniProt P62195 2 EQUAL 406 EQUAL Reactome Database ID Release 81 68780 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=68780 Reactome R-HSA-68780 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-68780.2 1 p31 PSMD8 26S proteasome non-ATPase regulatory subunit 8 26S proteasome regulatory subunit S14 Reactome DB_ID: 68808 UniProt:P48556 PSMD8 PSMD8 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD8, a base containing 6 ATPases and few additional components. Interacts with DDI2 (PubMed:29290612). Interacts with TASOR (By similarity).SIMILARITY Belongs to the proteasome subunit S14 family.CAUTION It is uncertain whether Met-1 or Met-64 is the initiator. UniProt P48556 1 EQUAL 350 EQUAL Reactome Database ID Release 81 68808 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=68808 Reactome R-HSA-68808 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-68808.2 1 p27K PSMA6 Proteasome subunit alpha type 6 Proteasome iota chain Macropain iota chain Multicatalytic endopeptidase complex iota chain 27 kDa prosomal protein PROS-27 Reactome DB_ID: 68734 UniProt:P60900 PSMA6 PSMA6 PROS27 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with ALKBH4 (PubMed:23145062).SIMILARITY Belongs to the peptidase T1A family. UniProt P60900 1 EQUAL 246 EQUAL Reactome Database ID Release 81 68734 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=68734 Reactome R-HSA-68734 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-68734.2 1 PSMB3 Proteasome subunit beta type 3 Proteasome theta chain Proteasome chain 13 Proteasome component C10-II Reactome DB_ID: 68747 UniProt:P49720 PSMB3 PSMB3 FUNCTION Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.INDUCTION Up-regulated in asthenozoospermic sperm.SIMILARITY Belongs to the peptidase T1B family. UniProt P49720 2 EQUAL 205 EQUAL Reactome Database ID Release 81 68747 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=68747 Reactome R-HSA-68747 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-68747.2 1 PSMA7 Proteasome subunit alpha type 7 Proteasome subunit RC6-1 Proteasome subunit XAPC7 Reactome DB_ID: 68736 UniProt:O14818 PSMA7 PSMA7 HSPC FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Inhibits the transactivation function of HIF-1A under both normoxic and hypoxia-mimicking conditions. The interaction with EMAP2 increases the proteasome-mediated HIF-1A degradation under the hypoxic conditions. Plays a role in hepatitis C virus internal ribosome entry site-mediated translation. Mediates nuclear translocation of the androgen receptor (AR) and thereby enhances androgen-mediated transactivation. Promotes MAVS degradation and thereby negatively regulates MAVS-mediated innate immune response.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. PSMA7 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly (PubMed:16251969). Interacts with HIF1A. Interacts with RAB7A (PubMed:14998988). Interacts with PRKN (PubMed:15987638). Interacts with ABL1 and ABL2 (PubMed:16678104). Interacts with EMAP2 (PubMed:19362550). Interacts with MAVS (PubMed:19734229).SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.SUBUNIT (Microbial infection) Interacts with hepatitis B virus X protein (HBX).INDUCTION Down-regulated by the ribozyme Rz3'X. Up-regulated in colorectal cancer tissues.PTM Phosphorylation by ABL1 or ABL2 leads to an inhibition of proteasomal activity and cell cycle transition blocks.SIMILARITY Belongs to the peptidase T1A family. UniProt O14818 1 EQUAL 248 EQUAL Reactome Database ID Release 81 68736 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=68736 Reactome R-HSA-68736 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-68736.2 1 PSMB10 Proteasome subunit beta type 10 Proteasome subunit beta type 10 precursor Proteasome MECl-1 Macropain subunit MECl-1 Multicatalytic endopeptidase complex subunit MECl-1 Reactome DB_ID: 68741 UniProt:P40306 PSMB10 PSMB10 LMP10 MECL1 FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB7. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.DEVELOPMENTAL STAGE Highly expressed in immature dendritic cells (at protein level).INDUCTION Up-regulated by IFNG/IFN-gamma (at protein level). Up-regulated by IRF1. Up-regulated by TNF (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Up-regulated by CD40L via the NFKB1 pathway in cancer cells.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.SIMILARITY Belongs to the peptidase T1B family. UniProt P40306 40 EQUAL 273 EQUAL Reactome Database ID Release 81 68741 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=68741 Reactome R-HSA-68741 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-68741.2 1 PSMC3 26S protease regulatory subunit 6A TAT-binding protein 1 TBP-1 Proteasome subunit P50 Reactome DB_ID: 68774 UniProt:P17980 PSMC3 PSMC3 TBP1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC3 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC3 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with PAAF1 (PubMed:15831487).SUBUNIT (Microbial infection) Interacts with HIV-1 Tat.PTM Sumoylated by UBE2I in response to MEKK1-mediated stimuli.SIMILARITY Belongs to the AAA ATPase family. UniProt P17980 1 EQUAL 439 EQUAL Reactome Database ID Release 81 68774 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=68774 Reactome R-HSA-68774 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-68774.2 1 PSMB1 Proteasome subunit beta type 1 Proteasome component C5 Macropain subunit C5 Multicatalytic endopeptidase complex subunit C5 Proteasome gamma chain Reactome DB_ID: 68738 UniProt:P20618 PSMB1 PSMB1 PSC5 FUNCTION Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with SERPINB2. Interacts with RFPL4A (By similarity).SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.SIMILARITY Belongs to the peptidase T1B family. UniProt P20618 29 EQUAL 241 EQUAL Reactome Database ID Release 81 68738 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=68738 Reactome R-HSA-68738 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-68738.2 1 PSMB11 Proteasome subunit beta type-11 PSB11_HUMAN Reactome DB_ID: 947607 UniProt:A5LHX3 PSMB11 PSMB11 FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. Incorporated instead of PSMB5 or PSMB8, this unit reduces the chymotrypsin-like activity of the proteasome (By similarity). Plays a pivotal role in development of CD8-positive T cells (By similarity).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Incorporated instead of PSMB5 and PSMB8.SIMILARITY Belongs to the peptidase T1B family. UniProt A5LHX3 50 EQUAL 300 EQUAL Reactome Database ID Release 81 947607 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=947607 Reactome R-HSA-947607 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-947607.1 1 PSMD3 26S proteasome non-ATPase regulatory subunit 3 26S proteasome regulatory subunit S3 Proteasome subunit p58 Reactome DB_ID: 68798 UniProt:O43242 PSMD3 PSMD3 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD3, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Interacts with UBQLN1 (via ubiquitin-like domain) (PubMed:15147878). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the proteasome subunit S3 family. UniProt O43242 1 EQUAL 534 EQUAL Reactome Database ID Release 81 68798 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=68798 Reactome R-HSA-68798 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-68798.2 1 PSMC4 26S protease regulatory subunit 6B MIP224 MB67 interacting protein TAT-binding protein-7 TBP-7 Reactome DB_ID: 68777 UniProt:P43686 PSMC4 PSMC4 MIP224 TBP7 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC4 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC4 and few additional components (PubMed:27428775,PubMed:27342858). Interacts with NR1I3. Interacts with PAAF1 (PubMed:15831487). Interacts with TRIM5 (PubMed:22078707). Interacts with ZFAND1 (PubMed:29804830).SIMILARITY Belongs to the AAA ATPase family. UniProt P43686 1 EQUAL 418 EQUAL Reactome Database ID Release 81 68777 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=68777 Reactome R-HSA-68777 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-68777.2 1 PSMB6 Proteasome subunit beta type 6 Proteasome subunit beta type 6 precursor Proteasome delta chain Macropain delta chain Multicatalytic endopeptidase complex delta chain Proteasome subunit Y Reactome DB_ID: 68756 UniProt:P28072 PSMB6 PSMB6 LMPY Y FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB6 displays a peptidylglutamyl-hydrolizing activity also termed postacidic or caspase-like activity, meaning that the peptides bond hydrolysis occurs directly after acidic residues.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.INDUCTION Down-regulated by IFNG/IFN-gamma (at protein level). Up-regulated in anaplastic thyroid cancer cell lines.SIMILARITY Belongs to the peptidase T1B family. UniProt P28072 35 EQUAL 239 EQUAL Reactome Database ID Release 81 68756 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=68756 Reactome R-HSA-68756 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-68756.2 1 PSMD9 26S proteasome non-ATPase regulatory subunit 9 26S proteasome regulatory subunit p27 Reactome DB_ID: 68810 UniProt:O00233 PSMD9 PSMD9 FUNCTION Acts as a chaperone during the assembly of the 26S proteasome, specifically of the base subcomplex of the PA700/19S regulatory complex (RC). During the base subcomplex assembly is part of an intermediate PSMD9:PSMC6:PSMC3 module, also known as modulator trimer complex; PSMD9 is released during the further base assembly process.SUBUNIT Interacts with PSMC3. Part of a transient complex (modulator) containing PSMD9, PSMC6 and PSMC3 formed during the assembly of the 26S proteasome.TISSUE SPECIFICITY Expressed in all tissues tested, highly expressed in liver and kidney.SIMILARITY Belongs to the proteasome subunit p27 family.CAUTION Was initially identified as a component of the 26S proteasome. UniProt O00233 1 EQUAL 223 EQUAL Reactome Database ID Release 81 68810 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=68810 Reactome R-HSA-68810 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-68810.2 1 PSMC2 26S protease regulatory subunit 7 MSS1 protein Reactome DB_ID: 68771 UniProt:P35998 PSMC2 PSMC2 MSS1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC2 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP) (PubMed:27428775, PubMed:27342858). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC2 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with NDC80/HEC; this interaction is detected only during M phase (PubMed:9295362, PubMed:10409732). Interacts and SQSTM1 (PubMed:15340068). Interacts with PAAF1 (PubMed:15831487). Directly interacts with TRIM5 (PubMed:22078707).SUBUNIT (Microbial infection) Interacts with HIV-1 Tat.INDUCTION Expression is not cell cycle-dependent and occurs throughout the cell cycle.PTM Monoubiquitinated by RNF181.SIMILARITY Belongs to the AAA ATPase family. UniProt P35998 2 EQUAL 433 EQUAL Reactome Database ID Release 81 68771 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=68771 Reactome R-HSA-68771 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-68771.2 1 p42A PSMD6 26S proteasome non-ATPase regulatory subunit 6 26S proteasome regulatory subunit S10 Proteasome regulatory particle subunit p44S10 Reactome DB_ID: 68804 UniProt:Q15008 PSMD6 PSMD6 KIAA0107 PFAAP4 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD6, a base containing 6 ATPases and few additional components.SIMILARITY Belongs to the proteasome subunit S10 family. UniProt Q15008 1 EQUAL 389 EQUAL Reactome Database ID Release 81 68804 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=68804 Reactome R-HSA-68804 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-68804.2 1 PSME4 Proteasome activator complex subunit 4 PSME4_HUMAN Reactome DB_ID: 947606 UniProt:Q14997 PSME4 PSME4 KIAA0077 FUNCTION Associated component of the proteasome that specifically recognizes acetylated histones and promotes ATP- and ubiquitin-independent degradation of core histones during spermatogenesis and DNA damage response. Recognizes and binds acetylated histones via its bromodomain-like (BRDL) region and activates the proteasome by opening the gated channel for substrate entry. Binds to the core proteasome via its C-terminus, which occupies the same binding sites as the proteasomal ATPases, opening the closed structure of the proteasome via an active gating mechanism. Component of the spermatoproteasome, a form of the proteasome specifically found in testis: binds to acetylated histones and promotes degradation of histones, thereby participating actively to the exchange of histones during spermatogenesis. Also involved in DNA damage response in somatic cells, by promoting degradation of histones following DNA double-strand breaks.SUBUNIT Homodimer. Interacts with the 20S and 26S proteasomes. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.DOMAIN The bromodomain-like (BRDL) region specifically recognizes and binds acetylated histones.SIMILARITY Belongs to the BLM10 family. UniProt Q14997 1 EQUAL 1843 EQUAL Reactome Database ID Release 81 947606 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=947606 Reactome R-HSA-947606 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-947606.1 1 RPN11 PSMD14 26S proteasome-associated pad1 homolog 26S proteasome regulatory subunit RPN11 Reactome DB_ID: 68722 UniProt:O00487 PSMD14 PSMD14 POH1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. The PSMD14 subunit is a metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains within the complex. Plays a role in response to double-strand breaks (DSBs): acts as a regulator of non-homologous end joining (NHEJ) by cleaving 'Lys-63'-linked polyubiquitin, thereby promoting retention of JMJD2A/KDM4A on chromatin and restricting TP53BP1 accumulation. Also involved in homologous recombination repair by promoting RAD51 loading.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD4, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Within the complex, PSMD4 interacts with subunit PSMD7 through their respective MPN domain. Interacts with TXNL1 (PubMed:19349277).TISSUE SPECIFICITY Widely expressed. Highest levels in heart and skeletal muscle.SIMILARITY Belongs to the peptidase M67A family. PSMD14 subfamily. UniProt O00487 1 EQUAL 310 EQUAL Reactome Database ID Release 81 68722 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=68722 Reactome R-HSA-68722 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-68722.3 1 PSMA2 Proteasome subunit alpha type 2 Proteasome component C3 Macropain subunit C3 Multicatalytic endopeptidase complex subunit C3 Reactome DB_ID: 68726 UniProt:P25787 PSMA2 PSMA2 HC3 PSC3 FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.INDUCTION Down-regulated by antioxidants BO-653 and probucol. Down-regulated in response to enterovirus 71 (EV71) infection (at protein level).PTM Phosphorylated on tyrosine residues; which may be important for nuclear import.SIMILARITY Belongs to the peptidase T1A family. UniProt P25787 2 EQUAL 234 EQUAL Reactome Database ID Release 81 68726 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=68726 Reactome R-HSA-68726 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-68726.2 1 PSMA8 Proteasome subunit alpha type-7-like PSA7L_HUMAN Reactome DB_ID: 947610 UniProt:Q8TAA3 PSMA8 PSMA8 PSMA7L FUNCTION Component of the spermatoproteasome, a proteasome specifically found in testis that promotes acetylation-dependent degradation of histones, thereby participating actively to the exchange of histones during spermatogenesis. The proteasome is a protein complex that degrades unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Required for 20S core proteasome assembly, essential for the degradation of meiotic proteins RAD51 and RPA1 at late prophase I and the progression of meiosis I during spermatogenesis. Localizes to the synaptonemal complex, a 'zipper'-like structure that holds homologous chromosome pairs in synapsis during meiotic prophase I.SUBUNIT Component of the outer alpha-ring of the 20S proteasome core which is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The catalytic chamber with the active sites is on the inside of the barrel. Interacts with canonical subunits of the spermatoproteasome, including proteasome activators PSME4 (also called PA200) and PSME3 (also called PA28-gamma). Interacts with proteasome-interacting proteins chaperones, ubiquitin ligases and ubiquitin specific proteases. Interacts with meiotic proteins cyclin dependent kinase CDK1 and the ATPase TRIP13 as well as proteins of the synaptonemal complex SIX6OS1 and SYCE3.SIMILARITY Belongs to the peptidase T1A family. UniProt Q8TAA3 1 EQUAL 256 EQUAL Reactome Database ID Release 81 947610 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=947610 Reactome R-HSA-947610 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-947610.1 1 PSMD2 26S proteasome non-ATPase regulatory subunit 2 26S proteasome regulatory subunit S2 26S proteasome subunit p97 Tumor necrosis factor type 1 receptor associated protein 2 55.11 protein Reactome DB_ID: 68796 UniProt:Q13200 PSMD2 PSMD2 TRAP2 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.FUNCTION Binds to the intracellular domain of tumor necrosis factor type 1 receptor. The binding domain of TRAP1 and TRAP2 resides outside the death domain of TNFR1.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD2 (PubMed:27428775, PubMed:27342858). Interacts with RPGRIP1L (By similarity). Interacts with CRY1 in a KDM8-dependent manner (By similarity).TISSUE SPECIFICITY Found in skeletal muscle, liver, heart, brain, kidney, pancreas, lung and placenta.SIMILARITY Belongs to the proteasome subunit S2 family. UniProt Q13200 1 EQUAL 908 EQUAL Reactome Database ID Release 81 68796 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=68796 Reactome R-HSA-68796 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-68796.2 1 PSMF1 Proteasome inhibitor PI31 subunit hPI31 Reactome DB_ID: 68818 UniProt:Q92530 PSMF1 PSMF1 FUNCTION Plays an important role in control of proteasome function. Inhibits the hydrolysis of protein and peptide substrates by the 20S proteasome. Also inhibits the activation of the proteasome by the proteasome regulatory proteins PA700 and PA28.SUBUNIT Monomer and homodimer. Interacts with FBXO7. Interacts with the 20S proteasome.SIMILARITY Belongs to the proteasome inhibitor PI31 family. UniProt Q92530 1 EQUAL 271 EQUAL Reactome Database ID Release 81 68818 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=68818 Reactome R-HSA-68818 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-68818.2 1 PSMC1 26S protease regulatory subunit 4 P26s4 Reactome DB_ID: 68768 UniProt:P62191 PSMC1 PSMC1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC1 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC1 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with SCA7 (PubMed:11734547). Interacts with NGLY1 (PubMed:15358861). Interacts with PAAF1 (PubMed:15831487).SIMILARITY Belongs to the AAA ATPase family. UniProt P62191 2 EQUAL 440 EQUAL Reactome Database ID Release 81 68768 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=68768 Reactome R-HSA-68768 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-68768.2 1 PSMB9 Proteasome subunit beta type 9 Proteasome subunit beta type 9 precursor Proteasome chain 7 Macropain chain 7 Multicatalytic endopeptidase complex chain 7 RING12 protein Low molecular mass protein 2 Reactome DB_ID: 68765 UniProt:P28065 PSMB9 PSMB9 LMP2 PSMB6i RING12 FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Replacement of PSMB6 by PSMB9 increases the capacity of the immunoproteasome to cleave model peptides after hydrophobic and basic residues.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB6. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.DEVELOPMENTAL STAGE Highly expressed in immature dendritic cells (at protein level).INDUCTION Up-regulated by interferon gamma (at protein level). Up-regulated by IRF1. Up-regulated by tumor necrosis factor-alpha (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Up-regulated by heat shock treatment. Up-regulated by CD40L via the NFKB1 pathway in cancer cells.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.MISCELLANEOUS Encoded in the MHC class II region.MISCELLANEOUS A model for self-activation in which residue Thr-21 serves as nucleophile and Lys-53 as proton donor/acceptor has been proposed. Subunit processing of mammalian beta-subunits proceeds via a novel ordered two-step mechanism involving autocatalysis.SIMILARITY Belongs to the peptidase T1B family. UniProt P28065 21 EQUAL 219 EQUAL Reactome Database ID Release 81 68765 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=68765 Reactome R-HSA-68765 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-68765.2 1 p44 PSMC6 26S protease regulatory subunit S10B Proteasome subunit p42 Conserved ATPase domain protein 44 CADp44 Reactome DB_ID: 68783 UniProt:P62333 PSMC6 PSMC6 SUG2 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC6 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC6 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with PAAF1 (PubMed:15831487).SIMILARITY Belongs to the AAA ATPase family.CAUTION Alternative initiation from an upstream conserved methionine cannot be fully excluded but is not experimentally supported while initiation from the displayed methionine is supported by PubMed:17323924. UniProt P62333 1 EQUAL 389 EQUAL Reactome Database ID Release 81 68783 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=68783 Reactome R-HSA-68783 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-68783.2 1 PSME2 Proteasome activator complex subunit 2 Proteasome activator 28-beta subunit PA28beta PA28b Activator of multicatalytic protease subunit 2 11S regulator complex beta subunit REG-beta Reactome DB_ID: 68814 UniProt:Q9UL46 PSME2 PSME2 FUNCTION Implicated in immunoproteasome assembly and required for efficient antigen processing. The PA28 activator complex enhances the generation of class I binding peptides by altering the cleavage pattern of the proteasome.SUBUNIT Heterodimer of PSME1 and PSME2, which forms a hexameric ring.INDUCTION By IFNG/IFN-gamma.SIMILARITY Belongs to the PA28 family. UniProt Q9UL46 2 EQUAL 239 EQUAL Reactome Database ID Release 81 68814 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=68814 Reactome R-HSA-68814 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-68814.2 1 RPN2 PSMD1 26S proteasome non-ATPase regulatory subunit 1 26S proteasome regulatory subunit S1 26S proteasome subunit p112 Reactome DB_ID: 68786 UniProt:Q99460 PSMD1 PSMD1 FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD1 (PubMed:27428775, PubMed:27342858). Interacts with ADRM1 (PubMed:16990800, PubMed:16906146). Interacts with ZFAND1 (PubMed:29804830).SIMILARITY Belongs to the proteasome subunit S1 family. UniProt Q99460 1 EQUAL 953 EQUAL Reactome Database ID Release 81 68786 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=68786 Reactome R-HSA-68786 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-68786.2 1 Reactome Database ID Release 81 68819 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=68819 Reactome R-HSA-68819 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-68819.2 GENE ONTOLOGY GO:0004175 Reactome Database ID Release 81 68824 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=68824 Reactome Database ID Release 81 264458 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=264458 Reactome R-HSA-264458 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-264458.2 Reactome Database ID Release 81 349425 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=349425 Reactome R-HSA-349425 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-349425.2 Reactome Database ID Release 81 69541 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=69541 Reactome R-HSA-69541 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-69541.5 11331603 Pubmed 2001 ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage. Maya, R Balass, M Kim, ST Shkedy, D Leal, JF Shifman, O Moas, M Buschmann, T Ronai, Z Shiloh, Y Kastan, MB Katzir, E Oren, M Genes Dev 15:1067-77 Transcriptional activation of p53 responsive genes p53 causes G1 arrest by inducing the expression of a cell cycle inhibitor, p21 (El-Deiry et al, 1993; Harper et al, 1993; Xiong et al, 1993). P21 binds and inactivates Cyclin-Cdk complexes that mediate G1/S progression, resulting in lack of phosphorylation of Rb, E2F sequestration and cell cycle arrest at the G1/S transition. Mice with a homozygous deletion of p21 gene are deficient in their ability to undergo a G1/S arrest in response to DNA damage (Deng et al, 1995). Transcriptional activation of cell cycle inhibitor p21 Both p53-independent and p53-dependent mechanisms of induction of p21 mRNA have been demonstrated. p21 is transcriptionally activated by p53 after DNA damage (el-Deiry et al., 1993). LEFT-TO-RIGHT TP53 binds ZNF385A ZNF385A (HZF) forms a complex with TP53 (p53), interacting with the DNA binding domain of TP53. The complex of TP53 and ZNF385A associates with p53 response elements of cell cycle arrest genes, such as CDKN1A (p21) and stimulates their transcription. Under prolonged stress, ZNF385A undergoes ubiquitination and proteasome-mediated degradation, which coincides with expression of TP53-regulated pro-apoptotic genes (Das et al. 2007). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 HZF ZNF385A Zinc finger protein 385A Retinal zinc finger protein Hematopoietic zinc finger protein HZF ZNF385 Reactome DB_ID: 6803421 UniProt:Q96PM9 ZNF385A ZNF385A HZF RZF ZNF385 FUNCTION RNA-binding protein that affects the localization and the translation of a subset of mRNA. May play a role in adipogenesis through binding to the 3'-UTR of CEBPA mRNA and regulation of its translation. Targets ITPR1 mRNA to dendrites in Purkinje cells, and may regulate its activity-dependent translation. With ELAVL1, binds the 3'-UTR of p53/TP53 mRNAs to control their nuclear export induced by CDKN2A. Hence, may regulate p53/TP53 expression and mediate in part the CDKN2A anti-proliferative activity. May also bind CCNB1 mRNA. Alternatively, may also regulate p53/TP53 activity through direct protein-protein interaction. Interacts with p53/TP53 and promotes cell-cycle arrest over apoptosis enhancing preferentially the DNA binding and transactivation of p53/TP53 on cell-cycle arrest target genes over proapoptotic target genes. May also regulate the ubiquitination and stability of CDKN1A promoting DNA damage-induced cell cycle arrest. Also plays a role in megakaryocytes differentiation.SUBUNIT Interacts with ELAVL1; the interaction is indirect, mRNA-dependent and may regulate p53/TP53 expression (By similarity). Interacts with p53/TP53; the interaction is direct and enhances p53/TP53 transactivation functions on cell-cycle arrest target genes, resulting in growth arrest.TISSUE SPECIFICITY Expressed predominantly in the retina.INDUCTION Up-regulated by p53/TP53 in response to DNA damage and oxidative stress.PTM Ubiquitinated upon prolonged exposure to genotoxic stress, which leads to proteasomal degradation of ZNF385A and releases p53/TP53 from cell-cycle arrest target gene promoters. UniProt Q96PM9 Reactome Database ID Release 81 6803421 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=6803421 Reactome R-HSA-6803421 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-6803421.1 p-S15,S20-TP53 Tetramer:ZNF385A Reactome DB_ID: 6803718 1 1 Reactome Database ID Release 81 6803718 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=6803718 Reactome R-HSA-6803718 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-6803718.1 Reactome Database ID Release 81 6803719 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=6803719 Reactome R-HSA-6803719 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-6803719.2 17719541 Pubmed 2007 Hzf Determines cell survival upon genotoxic stress by modulating p53 transactivation Das, Sanjeev Raj, Lakshmi Zhao, Bo Kimura, Yuki Bernstein, Alan Aaronson, Stuart A Lee, Sam W Cell 130:624-37 LEFT-TO-RIGHT TP53 in complex with ZNF385A binds the CDKN1A promoter TP53 (p53) binds at least two p53 response elements in the promoter of the CDKN1A (p21, WAF1) gene (El-Deiry et al. 1993, Espinosa et al. 2003). Formation of the complex of TP53 and ZNF385A (HZF) facilitates binding of TP53 to the CDKN1A promoter (Das et al. 2007). Authored: Orlic-Milacic, M, 2013-07-15 Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Samarajiwa, Shamith, 2013-09-03 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 p21 gene CDKN1A gene WAF1 gene CIP1 gene Reactome DB_ID: 3786256 ENSEMBL:ENSG00000124762 CDKN1A CDKN1A CAP20 CDKN1 CIP1 MDA6 PIC1 SDI1 WAF1 ENSEMBL ENSG00000124762 Reactome Database ID Release 81 3786256 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=3786256 Reactome R-HSA-3786256 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-3786256.2 p-S15,S20-TP53 Tetramer:ZNF385A:CDKN1A Gene Reactome DB_ID: 6803802 1 1 Reactome Database ID Release 81 6803802 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=6803802 Reactome R-HSA-6803802 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-6803802.1 Reactome Database ID Release 81 6803801 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=6803801 Reactome R-HSA-6803801 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-6803801.1 14580351 Pubmed 2003 p53 functions through stress- and promoter-specific recruitment of transcription initiation components before and after DNA damage Espinosa, Joaquín M Verdun, Ramiro E Emerson, Beverly M Mol. Cell 12:1015-27 8242752 Pubmed 1993 WAF1, a potential mediator of p53 tumor suppression. el-Deiry, WS Tokino, T Velculescu, VE Levy, DB Parsons, R Trent, JM Lin, D Mercer, WE Kinzler, KW Vogelstein, B Cell 75:817-25 LEFT-TO-RIGHT TP53 stimulates CDKN1A (p21) transcription Binding of TP53 (p53) to its response elements in the promoter of the CDKN1A (p21) gene stimulates CDKN1A transcription (El-Deiry et al. 1993). Binding of ZNF385A (HZF) to the DNA binding domain of TP53 facilitates CDKN1A induction and the consequent cell cycle arrest (Das et al. 2007). Authored: Matthews, L, 2006-09-29 13:54:26 Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Coqueret, O, 2006-10-06 08:59:06 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 p21 mRNA CDKN1A mRNA Reactome DB_ID: 6803386 ENSEMBL:ENST00000244741 CDKN1A CDKN1A ENSEMBL ENST00000244741 Reactome Database ID Release 81 6803386 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=6803386 Reactome R-HSA-6803386 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-6803386.1 Reactome Database ID Release 81 6803388 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=6803388 Reactome R-HSA-6803388 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-6803388.3 ACTIVATION activeUnit: #Complex17 Reactome Database ID Release 81 6803387 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=6803387 Reactome R-HSA-6803387 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-6803387.1 LEFT-TO-RIGHT PCBP4 binds the CDKN1A mRNA PCBP4 binds the 3'-UTR of the CDKN1A (p21) mRNA and reduces its stability (Scoumanne et al. 2011). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Reviewed: Donlon, Timothy, 2018-10-17 Reviewed: Bertaggia, Enrico, 2018-10-26 Edited: Orlic-Milacic, Marija, 2015-10-14 Edited: Orlic-Milacic, Marija, 2018-10-31 PCBP4 Poly(rC)-binding protein 4 MCG10 Alpha-CP4 Reactome DB_ID: 6803382 UniProt:P57723 PCBP4 PCBP4 FUNCTION Single-stranded nucleic acid binding protein that binds preferentially to oligo dC. UniProt P57723 1 EQUAL 403 EQUAL Reactome Database ID Release 81 6803382 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=6803382 Reactome R-HSA-6803382 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-6803382.1 PCBP4:CDKN1A mRNA Reactome DB_ID: 6803405 1 1 Reactome Database ID Release 81 6803405 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=6803405 Reactome R-HSA-6803405 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-6803405.1 Reactome Database ID Release 81 6803403 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=6803403 Reactome R-HSA-6803403 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-6803403.2 20817677 Pubmed 2011 The cyclin-dependent kinase inhibitor p21 is regulated by RNA-binding protein PCBP4 via mRNA stability Scoumanne, Ariane Cho, Seong Jun Zhang, Jin Chen, Xinbin Nucleic Acids Res. 39:213-24 LEFT-TO-RIGHT PCBP4 modulates CDKN1A translation PCBP4 binding to the 3'-UTR of the CDKN1A (p21) mRNA reduces half-life of the CDKN1A mRNA and the amount of CDKN1A protein. Upon DNA damage, TP53-mediated induction of CDKN1A is rapid, while the induction of PCBP4 is more gradual. It is hypothesized that, under prolonged stress, PCBP4-mediated down-regulation of CDKN1A may switch from G1 cell cycle arrest to G2 arrest, which may precede apoptosis (Scoumanne et al. 2011). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Reviewed: Donlon, Timothy, 2018-10-17 Reviewed: Bertaggia, Enrico, 2018-10-26 Edited: Orlic-Milacic, Marija, 2015-10-14 Edited: Orlic-Milacic, Marija, 2018-10-31 p21 CDKN1A Reactome DB_ID: 182585 UniProt:P38936 CDKN1A CDKN1A CAP20 CDKN1 CIP1 MDA6 PIC1 SDI1 WAF1 FUNCTION May be involved in p53/TP53 mediated inhibition of cellular proliferation in response to DNA damage. Binds to and inhibits cyclin-dependent kinase activity, preventing phosphorylation of critical cyclin-dependent kinase substrates and blocking cell cycle progression. Functions in the nuclear localization and assembly of cyclin D-CDK4 complex and promotes its kinase activity towards RB1. At higher stoichiometric ratios, inhibits the kinase activity of the cyclin D-CDK4 complex. Inhibits DNA synthesis by DNA polymerase delta by competing with POLD3 for PCNA binding (PubMed:11595739). Plays an important role in controlling cell cycle progression and DNA damage-induced G2 arrest (PubMed:9106657).SUBUNIT Interacts with HDAC1; the interaction is prevented by competitive binding of C10orf90/FATS to HDAC1 facilitating acetylation and protein stabilization of CDKN1A/p21 (By similarity). Interacts with MKRN1 (PubMed:19536131). Interacts with PSMA3 (PubMed:11350925). Interacts with PCNA (PubMed:11595739, PubMed:18794347, PubMed:18703516, PubMed:8861913). Component of the ternary complex, cyclin D-CDK4-CDKN1A. Interacts (via its N-terminal domain) with CDK4; the interaction promotes the assembly of the cyclin D-CDK4 complex, its nuclear translocation and promotes the cyclin D-dependent enzyme activity of CDK4 (PubMed:9106657). Binding to CDK2 leads to CDK2/cyclin E inactivation at the G1-S phase DNA damage checkpoint, thereby arresting cells at the G1-S transition during DNA repair (PubMed:19445729). Interacts with PIM1 (PubMed:12431783). Interacts with STK11 and NUAK1 (PubMed:25329316). Interacts wih DTL (PubMed:23213251). Interacts with isoform 1 and isoform 2 of TRIM39 (PubMed:23213251).TISSUE SPECIFICITY Expressed in all adult tissues, with 5-fold lower levels observed in the brain.INDUCTION Activated by p53/TP53, mezerein (antileukemic compound) and IFNB1. Repressed by HDAC1.DOMAIN The PIP-box K+4 motif mediates both the interaction with PCNA and the recruitment of the DCX(DTL) complex: while the PIP-box interacts with PCNA, the presence of the K+4 submotif, recruits the DCX(DTL) complex, leading to its ubiquitination.DOMAIN The C-terminal is required for nuclear localization of the cyclin D-CDK4 complex.PTM Phosphorylation of Thr-145 by Akt or of Ser-146 by PKC impairs binding to PCNA. Phosphorylation at Ser-114 by GSK3-beta enhances ubiquitination by the DCX(DTL) complex. Phosphorylation of Thr-145 by PIM2 enhances CDKN1A stability and inhibits cell proliferation. Phosphorylation of Thr-145 by PIM1 results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. UV radiation-induced phosphorylation at Thr-80 by LKB1 and at Ser-146 by NUAK1 leads to its degradation.PTM Ubiquitinated by MKRN1; leading to polyubiquitination and 26S proteasome-dependent degradation. Ubiquitinated by the DCX(DTL) complex, also named CRL4(CDT2) complex, leading to its degradation during S phase or following UV irradiation. Ubiquitination by the DCX(DTL) complex is essential to control replication licensing and is PCNA-dependent: interacts with PCNA via its PIP-box, while the presence of the containing the 'K+4' motif in the PIP box, recruit the DCX(DTL) complex, leading to its degradation. Ubiquitination at Ser-2 leads to degradation by the proteasome pathway. Ubiquitinated by RNF114; leading to proteasomal degradation.PTM Acetylation leads to protein stability. Acetylated in vitro on Lys-141, Lys-154, Lys-161 and Lys-163. Deacetylation by HDAC1 is prevented by competitive binding of C10orf90/FATS to HDAC1 (By similarity).SIMILARITY Belongs to the CDI family. UniProt P38936 2 EQUAL 164 EQUAL Reactome Database ID Release 81 182585 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=182585 Reactome R-HSA-182585 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-182585.1 Reactome Database ID Release 81 6803411 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=6803411 Reactome R-HSA-6803411 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-6803411.5 INHIBITION activeUnit: #Protein97 Reactome Database ID Release 81 6803416 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=6803416 Reactome R-HSA-6803416 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-6803416.2 Reactome Database ID Release 81 69895 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=69895 Reactome R-HSA-69895 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-69895.3 Reactome Database ID Release 81 69560 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=69560 Reactome R-HSA-69560 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-69560.2 8259214 Pubmed 1994 p21 is a universal inhibitor of cyclin kinases. Xiong, Y Hannon, GJ Zhang, H Casso, D Kobayashi, R Beach, D Nature 366:701-4 8242751 Pubmed 1993 The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Harper, JW Adami, GR Wei, N Keyomarsi, K Elledge, SJ Cell 75:805-16 7664346 Pubmed 1995 Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Deng, C Zhang, P Harper, JW Elledge, SJ Leder, P Cell 82:675-84 LEFT-TO-RIGHT Inactivation of Cyclin E:Cdk2 complexes by p27/p21 During G1, the activity of cyclin-dependent kinases (CDKs) is controlled by the CDK inhibitors (CKIs) CDKN1A (p21) and CDKN1B (p27), thereby preventing premature entry into S phase (see Guardavaccaro and Pagano, 2006). The efficient recognition and ubiquitination of p27 by the SCF (Skp2) complex requires the formation of a trimeric complex containing p27 and cyclin E/A:Cdk2. Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Matthews, L, 2006-10-02 07:13:54 Edited: Orlic-Milacic, Marija, 2015-10-14 CCNE:CDK2 Cyclin E:Cdk2 complexes Reactome DB_ID: 68374 Converted from EntitySet in Reactome Cyclin E Reactome DB_ID: 187493 CCNE2 G1/S-Specific cyclin E2 Reactome DB_ID: 68367 UniProt:O96020 CCNE2 CCNE2 FUNCTION Essential for the control of the cell cycle at the late G1 and early S phase.SUBUNIT Interacts with the CDK2 (in vivo) and CDK3 (in vitro) protein kinases to form a serine/threonine kinase holoenzyme complex. The cyclin subunit imparts substrate specificity to the complex.TISSUE SPECIFICITY According to PubMed:9858585, highest levels of expression in adult testis, thymus and brain. Lower levels in placenta, spleen and colon. Consistently elevated levels in tumor-derived cells compared to non-transformed proliferating cells. According to PubMed:9840927: low levels in thymus, prostate, brain, skeletal muscle, and kidney. Elevated levels in lung. According to PubMed:9840943 highly expressed in testis, placenta, thymus and brain. In a lesser extent in small intestine and colon.INDUCTION Activated by papilloma viral oncoproteins E6 and E7 which bind to and inactivate p53 and Rb, respectively.PTM Phosphorylation by CDK2 triggers its release from CDK2 and degradation via the ubiquitin proteasome pathway.SIMILARITY Belongs to the cyclin family. Cyclin E subfamily. UniProt O96020 1 EQUAL 404 EQUAL Reactome Database ID Release 81 68367 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=68367 Reactome R-HSA-68367 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-68367.2 CCNE1 G1/S-specific cyclin E1 Reactome DB_ID: 68363 UniProt:P24864 CCNE1 CCNE1 CCNE FUNCTION Essential for the control of the cell cycle at the G1/S (start) transition.SUBUNIT Interacts with CDK2 protein kinase to form a serine/threonine kinase holoenzyme complex. The cyclin subunit imparts substrate specificity to the complex (PubMed:15660127). Found in a complex with CDK2, CABLES1 and CCNA1 (By similarity). Part of a complex consisting of UHRF2, CDK2 and CCNE1 (PubMed:15178429). Interacts directly with UHRF2; the interaction ubiquitinates CCNE1 and appears to occur independently of CCNE1 phosphorylation (PubMed:21952639). Interacts with INCA1 (PubMed:21540187).TISSUE SPECIFICITY Highly expressed in testis and placenta. Low levels in bronchial epithelial cells.PTM Phosphorylation of both Thr-395 by GSK3 and Ser-399 by CDK2 creates a high affinity degron recognized by FBXW7, and accelerates degradation via the ubiquitin proteasome pathway. Phosphorylation at Thr-77 creates a low affinity degron also recognized by FBXW7.PTM Ubiquitinated by UHRF2; appears to occur independently of phosphorylation.SIMILARITY Belongs to the cyclin family. Cyclin E subfamily. UniProt P24864 1 EQUAL 410 EQUAL Reactome Database ID Release 81 68363 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=68363 Reactome R-HSA-68363 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-68363.2 Reactome Database ID Release 81 187493 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=187493 Reactome R-HSA-187493 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-187493.1 1 CDK2 Cdk2 Cell division protein kinase 2 (EC 2.7.1.-)(p33 protein kinase)(CDK2) Cell division protein kinase 2 p33 protein kinase Reactome DB_ID: 68365 UniProt:P24941 CDK2 CDK2 CDKN2 FUNCTION Serine/threonine-protein kinase involved in the control of the cell cycle; essential for meiosis, but dispensable for mitosis. Phosphorylates CTNNB1, USP37, p53/TP53, NPM1, CDK7, RB1, BRCA2, MYC, NPAT, EZH2. Triggers duplication of centrosomes and DNA. Acts at the G1-S transition to promote the E2F transcriptional program and the initiation of DNA synthesis, and modulates G2 progression; controls the timing of entry into mitosis/meiosis by controlling the subsequent activation of cyclin B/CDK1 by phosphorylation, and coordinates the activation of cyclin B/CDK1 at the centrosome and in the nucleus. Crucial role in orchestrating a fine balance between cellular proliferation, cell death, and DNA repair in human embryonic stem cells (hESCs). Activity of CDK2 is maximal during S phase and G2; activated by interaction with cyclin E during the early stages of DNA synthesis to permit G1-S transition, and subsequently activated by cyclin A2 (cyclin A1 in germ cells) during the late stages of DNA replication to drive the transition from S phase to mitosis, the G2 phase. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. Phosphorylates CABLES1 (By similarity). Cyclin E/CDK2 prevents oxidative stress-mediated Ras-induced senescence by phosphorylating MYC. Involved in G1-S phase DNA damage checkpoint that prevents cells with damaged DNA from initiating mitosis; regulates homologous recombination-dependent repair by phosphorylating BRCA2, this phosphorylation is low in S phase when recombination is active, but increases as cells progress towards mitosis. In response to DNA damage, double-strand break repair by homologous recombination a reduction of CDK2-mediated BRCA2 phosphorylation. Phosphorylation of RB1 disturbs its interaction with E2F1. NPM1 phosphorylation by cyclin E/CDK2 promotes its dissociates from unduplicated centrosomes, thus initiating centrosome duplication. Cyclin E/CDK2-mediated phosphorylation of NPAT at G1-S transition and until prophase stimulates the NPAT-mediated activation of histone gene transcription during S phase. Required for vitamin D-mediated growth inhibition by being itself inactivated. Involved in the nitric oxide- (NO) mediated signaling in a nitrosylation/activation-dependent manner. USP37 is activated by phosphorylation and thus triggers G1-S transition. CTNNB1 phosphorylation regulates insulin internalization. Phosphorylates FOXP3 and negatively regulates its transcriptional activity and protein stability (By similarity). Phosphorylates CDK2AP2 (PubMed:12944431). Phosphorylates ERCC6 which is essential for its chromatin remodeling activity at DNA double-strand breaks (PubMed:29203878).ACTIVITY REGULATION Phosphorylation at Thr-14 or Tyr-15 inactivates the enzyme, while phosphorylation at Thr-160 activates it (PubMed:1396589). Inhibited by 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)), AG-024322, N-(4-Piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), R547 (Ro-4584820), purine, pyrimidine and pyridine derivatives, 2-aminopyrimidines, paullones, thiazo derivatives, macrocyclic quinoxalin-2-one, pyrazolo[1,5-a]-1,3,5-triazine, pyrazolo[1,5-a]pyrimidine, 2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine (roscovitine, seliciclib and CYC202), SNS-032 (BMS-387032), triazolo[1,5-a]pyrimidines, staurosporine and olomoucine. Stimulated by MYC. Inactivated by CDKN1A (p21).SUBUNIT Found in a complex with CABLES1, CCNA1 and CCNE1. Interacts with CABLES1 (By similarity). Interacts with UHRF2. Part of a complex consisting of UHRF2, CDK2 and CCNE1. Interacts with the Speedy/Ringo proteins SPDYA and SPDYC (PubMed:15611625). Interaction with SPDYA promotes kinase activation via a conformation change that alleviates obstruction of the substrate-binding cleft by the T-loop (PubMed:28666995). Found in a complex with both SPDYA and CDKN1B/KIP1 (PubMed:12972555, PubMed:28666995). Binds to RB1 and CDK7. Binding to CDKN1A (p21) leads to CDK2/cyclin E inactivation at the G1-S phase DNA damage checkpoint, thereby arresting cells at the G1-S transition during DNA repair. Associated with PTPN6 and beta-catenin/CTNNB1. Interacts with CACUL1. May interact with CEP63. Interacts with ANKRD17. Interacts with CEBPA (when phosphorylated) (PubMed:15107404). Forms a ternary complex with CCNA2 and CDKN1B; CDKN1B inhibits the kinase activity of CDK2 through conformational rearrangements (PubMed:8684460). Interacts with cyclins A, B1, B3, D, or E (PubMed:10499802, PubMed:10884347, PubMed:12185076, PubMed:23781148). Interacts with CDK2AP2 (PubMed:23781148).INDUCTION Induced transiently by TGFB1 at an early phase of TGFB1-mediated apoptosis.PTM Phosphorylated at Thr-160 by CDK7 in a CAK complex (PubMed:28666995). Phosphorylation at Thr-160 promotes kinase activity, whereas phosphorylation at Tyr-15 by WEE1 reduces slightly kinase activity. Phosphorylated on Thr-14 and Tyr-15 during S and G2 phases before being dephosphorylated by CDC25A.PTM Nitrosylated after treatment with nitric oxide (DETA-NO).SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. UniProt P24941 1 EQUAL 298 EQUAL Reactome Database ID Release 81 68365 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=68365 Reactome R-HSA-68365 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-68365.2 1 Reactome Database ID Release 81 68374 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=68374 Reactome R-HSA-68374 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-68374.2 Converted from EntitySet in Reactome p21,p27 CDKN1A,CDKN1B Reactome DB_ID: 182558 p27 CDKN1B Reactome DB_ID: 182563 UniProt:P46527 CDKN1B CDKN1B KIP1 FUNCTION Important regulator of cell cycle progression. Inhibits the kinase activity of CDK2 bound to cyclin A, but has little inhibitory activity on CDK2 bound to SPDYA (PubMed:28666995). Involved in G1 arrest. Potent inhibitor of cyclin E- and cyclin A-CDK2 complexes. Forms a complex with cyclin type D-CDK4 complexes and is involved in the assembly, stability, and modulation of CCND1-CDK4 complex activation. Acts either as an inhibitor or an activator of cyclin type D-CDK4 complexes depending on its phosphorylation state and/or stoichometry.SUBUNIT Forms a ternary complex composed of CCNE1, CDK2 and CDKN1B. Interacts directly with CCNE1; the interaction is inhibited by CDK2-dependent phosphorylation on Thr-187. Interacts with COPS5, subunit of the COP9 signalosome complex; the interaction leads to CDKN1B degradation. Interacts with NUP50; the interaction leads to nuclear import and degradation of phosphorylated CDKN1B. Interacts with CCND1 and SNX6 (By similarity). Interacts (Thr-198-phosphorylated form) with 14-3-3 proteins, binds strongly YWHAQ, weakly YWHAE and YWHAH, but not YWHAB nor YWHAZ; the interaction with YWHAQ results in translocation to the cytoplasm (PubMed:14504289). Interacts with AKT1 and LYN; the interactions lead to cytoplasmic mislocation, phosphorylation of CDKN1B and inhibition of cell cycle arrest (PubMed:12042314, PubMed:12244301, PubMed:17254966). Forms a ternary complex with CCNA2 and CDK2; CDKN1B inhibits the kinase activity of CDK2 through conformational rearrangements. Interacts (unphosphorylated form) with CDK2. Forms a complex with CDK2 and SPDYA, but does not directly interact with SPDYA (PubMed:12972555, PubMed:28666995). Forms a ternary complex composed of cyclin D, CDK4 and CDKN1B. Interacts (phosphorylated on Tyr-88 and Tyr-89) with CDK4; the interaction is required for cyclin D and CDK4 complex assembly, induces nuclear translocation and activates the CDK4 kinase activity. Interacts with GRB2 (PubMed:16195327). Interacts with PIM1 (PubMed:18593906). Identified in a complex with SKP1, SKP2 and CKS1B (PubMed:16209941). Interacts with UHMK1; the interaction leads to cytoplasmic mislocation, phosphorylation of CDKN1B and inhibition of cell cycle arrest (PubMed:12093740). Interacts also with CDK1 (PubMed:16007079). Dephosphorylated on Thr-187 by PPM1H, leading to CDKN1B stability (PubMed:22586611).TISSUE SPECIFICITY Expressed in all tissues tested. Highest levels in skeletal muscle, lowest in liver and kidney.INDUCTION Maximal levels in quiescence cells and early G(1). Levels decrease after mitogen stimulation as cells progress toward S-phase.DOMAIN A peptide sequence containing only AA 28-79 retains substantial Kip1 cyclin A/CDK2 inhibitory activity.PTM Phosphorylated; phosphorylation occurs on serine, threonine and tyrosine residues. Phosphorylation on Ser-10 is the major site of phosphorylation in resting cells, takes place at the G(0)-G(1) phase and leads to protein stability. Phosphorylation on other sites is greatly enhanced by mitogens, growth factors, cMYC and in certain cancer cell lines. The phosphorylated form found in the cytoplasm is inactivate. Phosphorylation on Thr-198 is required for interaction with 14-3-3 proteins. Phosphorylation on Thr-187, by CDK1 and CDK2 leads to protein ubiquitination and proteasomal degradation. Tyrosine phosphorylation promotes this process. Phosphorylation by PKB/AKT1 can be suppressed by LY294002, an inhibitor of the catalytic subunit of PI3K. Phosphorylation on Tyr-88 and Tyr-89 has no effect on binding CDK2, but is required for binding CDK4. Dephosphorylated on tyrosine residues by G-CSF.PTM Ubiquitinated; in the cytoplasm by the KPC complex (composed of RNF123/KPC1 and UBAC1/KPC2) and, in the nucleus, by SCF(SKP2). The latter requires prior phosphorylation on Thr-187. Ubiquitinated; by a TRIM21-containing SCF(SKP2)-like complex; leads to its degradation.PTM Subject to degradation in the lysosome. Interaction with SNX6 promotes lysosomal degradation (By similarity).MISCELLANEOUS Decreased levels of p27Kip1, mainly due to proteasomal degradation, are found in various epithelial tumors originating from lung, breast, colon, ovary, esophagus, thyroid and prostate.SIMILARITY Belongs to the CDI family. UniProt P46527 1 EQUAL 198 EQUAL Reactome Database ID Release 81 182563 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=182563 Reactome R-HSA-182563 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-182563.1 Reactome Database ID Release 81 182558 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=182558 Reactome R-HSA-182558 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-182558.2 Cyclin E:CDK2:p21,p27 Cyclin E:CDK2:CDKN1A,CDKN1B Reactome DB_ID: 68376 1 1 Reactome Database ID Release 81 68376 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=68376 Reactome R-HSA-68376 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-68376.2 ACTIVATION GENE ONTOLOGY GO:0004861 Reactome Database ID Release 81 188223 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=188223 Reactome Database ID Release 81 69562 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=69562 Reactome R-HSA-69562 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-69562.5 16262255 Pubmed 2005 Ubiquitination of p21Cip1/WAF1 by SCFSkp2: substrate requirement and ubiquitination site selection Wang, W Nacusi, L Sheaff, RJ Liu, X Biochemistry 44:14553-64 10323868 Pubmed 1999 Ubiquitination of p27 is regulated by Cdk-dependent phosphorylation and trimeric complex formation Montagnoli, A Fiore, F Eytan, E Carrano, AC Draetta, GF Hershko, A Pagano, Michele Genes Dev 13:1181-9 16600864 Pubmed 2006 Stabilizers and destabilizers controlling cell cycle oscillators Guardavaccaro, D Pagano, Michele Mol Cell 22:1-4 LEFT-TO-RIGHT Inactivation of Cyclin A:Cdk2 complexes by p27/p21 During G1, the activity of cyclin-dependent kinases (CDKs) is controlled by the CDK inhibitors (CKIs) CDKN1A (p21) and CDKN1B (p27), thereby preventing premature entry into S phase (Guardavaccaro and Pagano, 2006). Authored: Pagano, M, 2006-09-19 08:23:10 Reviewed: Coqueret, O, 2006-10-06 08:59:06 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Matthews, L, 2006-09-28 04:25:14 CCNA:CDK2 Cyclin A:Cdk2 complex Reactome DB_ID: 141608 1 Converted from EntitySet in Reactome CCNA Cyclin A Reactome DB_ID: 75202 CCNA1 Cyclin A1 Reactome DB_ID: 68891 UniProt:P78396 CCNA1 CCNA1 FUNCTION May be involved in the control of the cell cycle at the G1/S (start) and G2/M (mitosis) transitions. May primarily function in the control of the germline meiotic cell cycle and additionally in the control of mitotic cell cycle in some somatic cells.SUBUNIT Interacts with the CDK2 and the CDC2 protein kinases to form a serine/threonine kinase holoenzyme complex. The cyclin subunit imparts substrate specificity to the complex. Does not bind CDK4 and CDK5 (in vitro). The cyclin A1-CDK2 complex interacts with transcription factor E2F-1 and RB proteins. Found in a complex with CDK2, CABLES1 and CCNE1 (By similarity). Interacts with INCA1 (PubMed:15159402, PubMed:21540187). Interacts with KLHDC9 (PubMed:15159402).TISSUE SPECIFICITY Very high levels in testis and very low levels in brain. Also found in myeloid leukemia cell lines.DEVELOPMENTAL STAGE Expression increases in early G1 phase and reaches highest levels during the S and G2/M phases.PTM Polyubiquitinated via 'Lys-11'-linked ubiquitin by the anaphase-promoting complex (APC/C), leading to its degradation by the proteasome. Deubiquitinated and stabilized by USP37 enables entry into S phase.SIMILARITY Belongs to the cyclin family. Cyclin AB subfamily. UniProt P78396 1 EQUAL 465 EQUAL Reactome Database ID Release 81 68891 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=68891 Reactome R-HSA-68891 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-68891.2 CCNA2 Cyclin A2 Cyclin A Reactome DB_ID: 68905 UniProt:P20248 CCNA2 CCNA2 CCN1 CCNA FUNCTION Cyclin which controls both the G1/S and the G2/M transition phases of the cell cycle. Functions through the formation of specific serine/threonine protein kinase holoenzyme complexes with the cyclin-dependent protein kinases CDK1 or CDK2. The cyclin subunit confers the substrate specificity of these complexes and differentially interacts with and activates CDK1 and CDK2 throughout the cell cycle.SUBUNIT Interacts with the CDK1 and CDK2 protein kinases to form serine/threonine kinase holoenzyme complexes (PubMed:1312467, PubMed:7630397, PubMed:8684460, PubMed:8756328). Interacts with CDK1 (hyperphosphorylated form in G1 and underphosphorylated forms in S and G2) (PubMed:1312467). Interacts with CDK2; the interaction increases from G1 to G2 (PubMed:1312467). Interacts (associated with CDK2 but not with CDK1) with SCAPER; regulates the activity of CCNA2/CDK2 by transiently maintaining CCNA2 in the cytoplasm (PubMed:17698606). Forms a ternary complex with CDK2 and CDKN1B; CDKN1B inhibits the kinase activity of CDK2 through conformational rearrangements (PubMed:8684460). Interacts with INCA1 (PubMed:21540187).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus protein UL32.DEVELOPMENTAL STAGE Accumulates steadily during G2 and is abruptly destroyed at mitosis. Not detected during the G1 phase of the cell cycle. It accumulates during the DNA synthesis/S phase and disappears as cells progress into mitosis, between prophase and metaphase (at protein level).PTM Polyubiquitinated via 'Lys-11'-linked ubiquitin by the anaphase-promoting complex (APC/C), leading to its degradation by the proteasome. Deubiquitinated and stabilized by USP37 enables entry into S phase.SIMILARITY Belongs to the cyclin family. Cyclin AB subfamily. UniProt P20248 1 EQUAL 432 EQUAL Reactome Database ID Release 81 68905 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=68905 Reactome R-HSA-68905 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-68905.2 Reactome Database ID Release 81 75202 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=75202 Reactome R-HSA-75202 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-75202.1 1 Reactome Database ID Release 81 141608 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=141608 Reactome R-HSA-141608 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-141608.2 Cyclin A:Cdk2:p21/p27 complex Reactome DB_ID: 187926 1 1 Reactome Database ID Release 81 187926 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=187926 Reactome R-HSA-187926 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-187926.1 ACTIVATION Reactome Database ID Release 81 187934 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=187934 Reactome R-HSA-187934 8 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-187934.8 7624798 Pubmed 1995 Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27 Pagano, Michele Tam, SW Theodoras, AM Beer-Romero, P Del Sal, G Chau, V Yew, PR Draetta, GF Rolfe, M Science 269:682-5 Reactome Database ID Release 81 69563 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=69563 Reactome R-HSA-69563 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-69563.3 9153395 Pubmed 1997 Mdm2 promotes the rapid degradation of p53. Haupt, Y Maya, R Kazaz, A Oren, M Nature 387:296-9 1423616 Pubmed 1992 A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Kastan, MB Zhan, Q el-Deiry, WS Carrier, F Jacks, T Walsh, WV Plunkett, BS Vogelstein, B Fornace, AJ Cell 71:587-97 9153396 Pubmed 1997 Regulation of p53 stability by Mdm2. Kubbutat, MH Jones, SN Vousden, KH Nature 387:299-303 8247533 Pubmed 1993 Ionizing radiation and UV induction of p53 protein by different pathways in ataxia-telangiectasia cells. Khanna, Kum Kum Lavin, MF Oncogene 8:3307-12 GENE ONTOLOGY GO:0006977 gene ontology term for cellular process MI MI:0359 Reactome Database ID Release 81 69580 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=69580 Reactome R-HSA-69580 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-69580.3 1323840 Pubmed 1992 Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Kuerbitz, SJ Plunkett, BS Walsh, WV Kastan, MB Proc Natl Acad Sci U S A 89:7491-5 p53-Independent G1/S DNA damage checkpoint The G1 arrest induced by DNA damage has been ascribed to the transcription factor and tumor suppressor protein p53. To be effective within minutes after DNA damage, induction of the G1 block should exploit transcription and protein synthesis independent mechanisms.<p>Upon exposure to ultraviolet light (UV) or ionizing radiation (IR), the abundance and activity of a protein, Cdc25A, rapidly decreases; this DNA damage response is not dependent on p53. The rapid destruction of Cdc25A phosphatase prevents entry of a cell into S-phase, by maintaining the CyclinE:Cdk2 complexes in their T14Y15 phosphorylated form. p53-Independent DNA Damage Response In response to DNA damage due to exposure to ultraviolet light or to ionizing radiation, Cdc25A is phosphorylated by Chk1 or Chk2. The phosphorylation of Cdc25A at ser-123, in response to DNA damage from ionizing radiation is a signal for ubiquitination and subsequent degradation of Cdc25A. The destruction of Cdc25A prevents the normal G1/S transition. Cdc25A is required for the activation of the Cyclin E:Cdk2 complexes via dephosphorylation.<p>Chk1 is activated in response to DNA damage due to uv light. However, the phosphorylation occurs at a different site. Ubiquitin Mediated Degradation of Phosphorylated Cdc25A cdc25A protein is degraded by the ubiquitin-proteasome machinery in both terminally differentiating and cycling cells (Bernardi et al. 2000). LEFT-TO-RIGHT 2.7.11.1 Phosphorylation of Cdc25A at Ser-123 by Chk2 Detection of DNA damage caused by ionizing radiation results in the phosphorylation of Cdc25A at Ser-123 by Chk2 (Mailand et al. 2001). CDC25A Cdc25A M-phase inducer phosphatase 1 (EC 3.1.3.48) (Dual specificity phosphatase Cdc25A) M-phase inducer phosphatase 1 Dual specificity phosphatase Cdc25A Reactome DB_ID: 143487 UniProt:P30304 CDC25A CDC25A FUNCTION Tyrosine protein phosphatase which functions as a dosage-dependent inducer of mitotic progression. Directly dephosphorylates CDK1 and stimulates its kinase activity. Also dephosphorylates CDK2 in complex with cyclin E, in vitro.ACTIVITY REGULATION Stimulated by B-type cyclins. Stimulated by PIM1-mediated phosphorylation.SUBUNIT Interacts with CCNB1/cyclin B1. Interacts with YWHAE/14-3-3 epsilon when phosphorylated. Interacts with CUL1 specifically when CUL1 is neddylated and active. Interacts with BTRC/BTRCP1 and FBXW11/BTRCP2. Interactions with CUL1, BTRC and FBXW11 are enhanced upon DNA damage. Interacts with PIM1. Interacts with CHEK2; mediates CDC25A phosphorylation and degradation in response to infrared-induced DNA damages. Interacts with HSP90AB1; prevents heat shock-mediated CDC25A degradation and contributes to cell cycle progression (PubMed:22843495).DOMAIN The phosphodegron motif mediates interaction with specific F-box proteins when phosphorylated. Putative phosphorylation sites at Ser-79 and Ser-82 appear to be essential for this interaction.PTM Phosphorylated by CHEK1 on Ser-76, Ser-124, Ser-178, Ser-279, Ser-293 and Thr-507 during checkpoint mediated cell cycle arrest. Also phosphorylated by CHEK2 on Ser-124, Ser-279, and Ser-293 during checkpoint mediated cell cycle arrest. Phosphorylation on Ser-178 and Thr-507 creates binding sites for YWHAE/14-3-3 epsilon which inhibits CDC25A. Phosphorylation on Ser-76, Ser-124, Ser-178, Ser-279 and Ser-293 may also promote ubiquitin-dependent proteolysis of CDC25A by the SCF complex. Phosphorylation of CDC25A at Ser-76 by CHEK1 primes it for subsequent phosphorylation at Ser-79, Ser-82 and Ser-88 by NEK11. Phosphorylation by NEK11 is required for BTRC-mediated polyubiquitination and degradation. Phosphorylation by PIM1 leads to an increase in phosphatase activity. Phosphorylated by PLK3 following DNA damage, leading to promote its ubiquitination and degradation.PTM Ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase complex that contains FZR1/CDH1 during G1 phase leading to its degradation by the proteasome. Ubiquitinated by a SCF complex containing BTRC and FBXW11 during S phase leading to its degradation by the proteasome. Deubiquitination by USP17L2/DUB3 leads to its stabilization.SIMILARITY Belongs to the MPI phosphatase family. UniProt P30304 1 EQUAL 524 EQUAL Reactome Database ID Release 81 143487 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=143487 Reactome R-HSA-143487 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-143487.1 p-S123-CDC25A phospho-Cdc25A Reactome DB_ID: 143488 123 EQUAL 1 EQUAL 524 EQUAL Reactome Database ID Release 81 143488 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=143488 Reactome R-HSA-143488 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-143488.1 ACTIVATION Reactome Database ID Release 81 69608 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=69608 Reactome R-HSA-69608 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-69608.5 11298456 Pubmed 2001 The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Mailand, N Syljuåsen, RG Lukas, J Nature 410:842-7 LEFT-TO-RIGHT 6.3.2.19 Ubiquitination of phosphorylated Cdc25A At the beginning of this reaction, 1 molecule of 'ubiquitin', and 1 molecule of 'phospho-Cdc25A' are present. At the end of this reaction, 1 molecule of 'Ubiquitinated Phospho-Cdc25A' is present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'ubiquitin-protein ligase activity' of 'Ubiquitin ligase' (Bernardi et al. 2000).<br> p-S123-CDC25A phospho-Cdc25A M-phase inducer phosphatase 1 Dual specificity phosphatase Cdc25A Reactome DB_ID: 69588 1 EQUAL 524 EQUAL Reactome Database ID Release 81 69588 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=69588 Reactome R-HSA-69588 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-69588.1 Ub-p-S123-CDC25A Ubiquitinated Phospho-Cdc25A Reactome DB_ID: 69589 1 1 Reactome Database ID Release 81 69589 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=69589 Reactome R-HSA-69589 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-69589.1 ACTIVATION Ubiquitin ligase Reactome DB_ID: 69593 Reactome Database ID Release 81 69593 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=69593 Reactome R-HSA-69593 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-69593.2 ChEBI 36080 Reactome Database ID Release 81 69594 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=69594 Reactome Database ID Release 81 69598 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=69598 Reactome R-HSA-69598 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-69598.5 10828887 Pubmed 2000 Cdc25A stability is controlled by the ubiquitin-proteasome pathway during cell cycle progression and terminal differentiation Bernardi, R Liebermann, DA Hoffman, B Oncogene 19:2447-54 LEFT-TO-RIGHT Proteolytic degradation of ubiquitinated-Cdc25A At the beginning of this reaction, 1 molecule of 'Ubiquitinated Phospho-Cdc25A' is present. At the end of this reaction, 1 molecule of 'Amino Acid' is present.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'endopeptidase activity' of '26S proteasome' (Bernardi et al. 2000).<br> ACTIVATION Reactome Database ID Release 81 69600 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=69600 Reactome R-HSA-69600 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-69600.3 LEFT-TO-RIGHT 2.7.11.1 Phosphorylation of Cdc25A at Ser-123 by Chk1 Detection of DNA damage caused by ionizing radiation results in the phosphorylation of Cdc25A at Ser-123 by Chk1, inhibiting Cdc25A. ACTIVATION phospho-Chk1 p-S317,S345-CHEK1 Serine/threonine-protein kinase Chk1 (EC 2.7.1.-) phosphorylated Serine/threonine-protein kinase Chk1 Reactome DB_ID: 113838 UniProt:O14757 CHEK1 CHEK1 CHK1 FUNCTION Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA (PubMed:11535615, PubMed:12446774, PubMed:12399544, PubMed:14559997, PubMed:14988723, PubMed:15311285, PubMed:15665856, PubMed:15650047, PubMed:32357935). May also negatively regulate cell cycle progression during unperturbed cell cycles (PubMed:11535615, PubMed:12446774, PubMed:12399544, PubMed:14559997, PubMed:14988723, PubMed:15311285, PubMed:15665856, PubMed:15650047). This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome (PubMed:11535615, PubMed:12446774, PubMed:12399544, PubMed:14559997, PubMed:14988723, PubMed:15311285, PubMed:15665856, PubMed:15650047). Recognizes the substrate consensus sequence [R-X-X-S/T] (PubMed:11535615, PubMed:12446774, PubMed:12399544, PubMed:14559997, PubMed:14988723, PubMed:15311285, PubMed:15665856, PubMed:15650047). Binds to and phosphorylates CDC25A, CDC25B and CDC25C (PubMed:9278511, PubMed:12676583, PubMed:14681206, PubMed:12676925, PubMed:12759351, PubMed:19734889, PubMed:14559997). Phosphorylation of CDC25A at 'Ser-178' and 'Thr-507' and phosphorylation of CDC25C at 'Ser-216' creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C (PubMed:9278511). Phosphorylation of CDC25A at 'Ser-76', 'Ser-124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A (PubMed:9278511, PubMed:12676583, PubMed:14681206, PubMed:12676925, PubMed:12759351, PubMed:19734889). Phosphorylation of CDC25A at 'Ser-76' primes the protein for subsequent phosphorylation at 'Ser-79', 'Ser-82' and 'Ser-88' by NEK11, which is required for polyubiquitination and degradation of CDCD25A (PubMed:9278511, PubMed:19734889, PubMed:20090422). Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression (PubMed:9278511). Also phosphorylates NEK6 (PubMed:18728393). Binds to and phosphorylates RAD51 at 'Thr-309', which promotes the release of RAD51 from BRCA2 and enhances the association of RAD51 with chromatin, thereby promoting DNA repair by homologous recombination (PubMed:15665856). Phosphorylates multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and promotes cell cycle arrest and suppression of cellular proliferation (PubMed:10673501, PubMed:15659650, PubMed:16511572). Also promotes repair of DNA cross-links through phosphorylation of FANCE (PubMed:17296736). Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A (PubMed:12660173, PubMed:12955071). This may enhance chromatin assembly both in the presence or absence of DNA damage (PubMed:12660173, PubMed:12955071). May also play a role in replication fork maintenance through regulation of PCNA (PubMed:18451105). May regulate the transcription of genes that regulate cell-cycle progression through the phosphorylation of histones (By similarity). Phosphorylates histone H3.1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes (By similarity). May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest (PubMed:17380128). Phosphorylates SPRTN, promoting SPRTN recruitment to chromatin (PubMed:31316063). Reduces replication stress and activates the G2/M checkpoint, by phosphorylating and inactivating PABIR1/FAM122A and promoting the serine/threonine-protein phosphatase 2A-mediated dephosphorylation and stabilization of WEE1 levels and activity (PubMed:33108758).ACTIVITY REGULATION Activated through phosphorylation predominantly by ATR but also by ATM in response to DNA damage or inhibition of DNA replication (PubMed:11390642, PubMed:12588868, PubMed:12676583, PubMed:12676962, PubMed:15665856, PubMed:19716789). Activation is modulated by several mediators including CLSPN, BRCA1 and FEM1B (PubMed:11836499, PubMed:12766152, PubMed:16963448, PubMed:19330022). Proteolytic cleavage at the C-terminus by SPRTN during normal DNA replication activates the protein kinase activity (PubMed:31316063).SUBUNIT Interacts (phosphorylated by ATR) with RAD51 (PubMed:15665856). Interacts with and phosphorylates CLSPN, an adapter protein that regulates the ATR-dependent phosphorylation of CHEK1 (PubMed:16963448). Interacts with BRCA1 (PubMed:11836499). Interacts with and phosphorylates CDC25A, CDC25B and CDC25C (PubMed:9278511). Interacts with FBXO6, which regulates CHEK1 (PubMed:19716789). Interacts with PPM1D, which regulates CHEK1 through dephosphorylation (PubMed:15870257). Interacts with TIMELESS; DNA damage-dependent (PubMed:15798197). Interacts with FEM1B; activates CHEK1 in response to stress (PubMed:19330022). Interacts with TLK1 (PubMed:12660173). Interacts with XPO1 and YWHAZ (PubMed:12676962). Interacts with CDK5RAP3; antagonizes CHEK1 (PubMed:19223857).TISSUE SPECIFICITY Expressed ubiquitously with the most abundant expression in thymus, testis, small intestine and colon.DOMAIN The autoinhibitory region (AIR) inhibits the activity of the kinase domain.PTM Phosphorylated by ATR in a RAD17-dependent manner in response to ultraviolet irradiation and inhibition of DNA replication. Phosphorylated by ATM in response to ionizing irradiation. ATM and ATR can both phosphorylate Ser-317 and Ser-345 and this results in enhanced kinase activity. Phosphorylation at Ser-345 induces a change in the conformation of the protein, activates the kinase activity and is a prerequisite for interaction with FBXO6 and subsequent ubiquitination at Lys-436. Phosphorylation at Ser-345 also increases binding to 14-3-3 proteins and promotes nuclear retention. Conversely, dephosphorylation at Ser-345 by PPM1D may contribute to exit from checkpoint mediated cell cycle arrest. Phosphorylation at Ser-280 by AKT1/PKB, may promote mono and/or diubiquitination. Also phosphorylated at undefined residues during mitotic arrest, resulting in decreased activity.PTM Ubiquitinated. Mono or diubiquitination promotes nuclear exclusion (By similarity). The activated form (phosphorylated on Ser-345) is polyubiquitinated at Lys-436 by some SCF-type E3 ubiquitin ligase complex containing FBXO6 promoting its degradation. Ubiquitination and degradation are required to terminate the checkpoint and ensure that activated CHEK1 does not accumulate as cells progress through S phase, when replication forks encounter transient impediments during normal DNA replication. 'Lys-63'-mediated ubiquitination by TRAF4 at Lys-132 activates cell cycle arrest and activation of DNA repair (PubMed:32357935).PTM Proteolytically cleaved at the C-terminus by SPRTN during normal DNA replication, thereby promoting CHEK1 removal from chromatin and activating the protein kinase activity.SIMILARITY Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. NIM1 subfamily. UniProt O14757 317 EQUAL 345 EQUAL 1 EQUAL 476 EQUAL Reactome Database ID Release 81 113838 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=113838 Reactome R-HSA-113838 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-113838.1 Reactome Database ID Release 81 143490 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=143490 Reactome Database ID Release 81 69604 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=69604 Reactome R-HSA-69604 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-69604.3 12399544 Pubmed 2002 Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints. Zhao, H Watkins, JL Piwnica-Worms, H Proc Natl Acad Sci U S A 99:14795-800 Reactome Database ID Release 81 69601 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=69601 Reactome R-HSA-69601 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-69601.3 Reactome Database ID Release 81 69610 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=69610 Reactome R-HSA-69610 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-69610.4 Reactome Database ID Release 81 69613 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=69613 Reactome R-HSA-69613 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-69613.2 10827953 Pubmed 2000 Rapid destruction of human Cdc25A in response to DNA damage. Mailand, N Lukas, C Syljuâsen, RG Welcker, M Lukas, J Science 288:1425-9 Reactome Database ID Release 81 69615 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=69615 Reactome R-HSA-69615 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-69615.2 G2/M Checkpoints G2/M checkpoints include the checks for damaged DNA, unreplicated DNA, and checks that ensure that the genome is replicated once and only once per cell cycle. If cells pass these checkpoints, they follow normal transition to the M phase. However, if any of these checkpoints fail, mitotic entry is prevented by specific G2/M checkpoint events.<p>The G2/M checkpoints can fail due to the presence of unreplicated DNA or damaged DNA. In such instances, the cyclin-dependent kinase, Cdc2(Cdk1), is maintained in its inactive, phosphorylated state, and mitotic entry is prevented. Events that ensure that origins of DNA replication fire once and only once per cell cycle are also an example of a G2/M checkpoint.<p>In the event of high levels of DNA damage, the cells may also be directed to undergo apopotosis (not covered). G2/M DNA damage checkpoint Throughout the cell cycle, the genome is constantly monitored for damage, resulting either from errors of replication, by-products of metabolism or through extrinsic sources such as ultra-violet or ionizing radiation. The different DNA damage checkpoints act to inhibit or maintain the inhibition of the relevant CDK that will control the next cell cycle transition. The G2 DNA damage checkpoint prevents mitotic entry solely through T14Y15 phosphorylation of Cdc2 (Cdk1). Failure of the G2 DNA damage checkpoint leads to catastrophic attempts to segregate unrepaired chromosomes. LEFT-TO-RIGHT 2.7.11.1 Recruitment and activation of Chk1 Chk1 is a checkpoint kinase activated during genotoxic stress. Like ATR, Chk1 is essential for viability in mammals. Targeted gene disruption in mice shows that loss of Chk1 causes peri-implantation embryonic lethality. Even though ATR-ATRIP not bound to ssDNA can phosphorylate Chk1, Chk1 activation is greatly enhanced when recruited to stalled replication forks by physical interaction with a modified form of claspin and the Rad9-Hus1-Rad1 sliding clamp. Activation of Chk1 occurs following phosphorylation of two sites (serine 317 and serine 345). Mutational analysis indicates that modification of both sites is essential for maximal kinase activity, while phosphorylation of only a single site causes only weak activation of Chk1. Following phosphorylation, Chk1 can diffuse away from the complex to further amplify the checkpoint signal. ATR appears to be the primary kinase activating Chk1 as conditions that activate ATR (ultraviolet irradiation or treatment with hydroxyurea) also activate Chk1. Stresses that activate ATM, e.g., ionizing irradiation, do not cause significant Chk1 activation. While the ATR and ATM pathways are distinct, there is interplay between the two. For example, double-strand DNA breaks can be processed in an ATM-dependent manner to generate structures that can cause ATR and hence Chk1 activation. The ATR and ATM pathways also have mechanistic similarities. Analogous to the Chk1 kinase existing downstream of ATR, the Chk2 checkpoint kinase is modified and activated by ATM. Although having distinct structures, Chk1 and Chk2 also have overlapping targets with some substrate sites phosphorylatable by both kinases (e.g., serine 20 of p53). Authored: Borowiec, JA, 2006-02-25 17:40:15 Edited: D'Eustachio, P, 2006-02-25 17:41:28 Chk1 CHEK1 Serine/threonine-protein kinase Chk1 (EC 2.7.1.-) Serine/threonine-protein kinase Chk1 Reactome DB_ID: 113826 1 EQUAL 476 EQUAL Reactome Database ID Release 81 113826 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=113826 Reactome R-HSA-113826 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-113826.1 ACTIVATION activeUnit: #Protein114 ATR:ATRIP ATR-ATRIP ATM- and rad3-related (ATR) ATR-interacting protein (ATRIP) Reactome DB_ID: 176269 ATRIP ATRIP monomer ATR interacting protein Reactome DB_ID: 176231 UniProt:Q8WXE1 ATRIP ATRIP AGS1 FUNCTION Required for checkpoint signaling after DNA damage. Required for ATR expression, possibly by stabilizing the protein.SUBUNIT Interacts with ATR (By similarity). Heterodimer with ATR. The heterodimer binds the RPA complex and is then recruited to single-stranded DNA. Interacts with CEP164 (via N-terminus). Interacts with CINP.TISSUE SPECIFICITY Ubiquitous.DOMAIN The EEXXXDDL motif is required for the interaction with catalytic subunit PRKDC and its recruitment to sites of DNA damage.PTM Phosphorylated by ATR.SIMILARITY Belongs to the ATRIP family.CAUTION The gene for this protein is either identical to or adjacent to that of TREX1. Some of the mRNAs that encode ATRIP also encode TREX1 in another reading frame. UniProt Q8WXE1 1 EQUAL 791 EQUAL Reactome Database ID Release 81 176231 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=176231 Reactome R-HSA-176231 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-176231.1 1 ATR Serine/threonine-protein kinase ATR ATR_HUMAN Reactome DB_ID: 912443 UniProt:Q13535 ATR ATR FRP1 FUNCTION Serine/threonine protein kinase which activates checkpoint signaling upon genotoxic stresses such as ionizing radiation (IR), ultraviolet light (UV), or DNA replication stalling, thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates BRCA1, CHEK1, MCM2, RAD17, RPA2, SMC1 and p53/TP53, which collectively inhibit DNA replication and mitosis and promote DNA repair, recombination and apoptosis. Phosphorylates 'Ser-139' of histone variant H2AX at sites of DNA damage, thereby regulating DNA damage response mechanism. Required for FANCD2 ubiquitination. Critical for maintenance of fragile site stability and efficient regulation of centrosome duplication. Positively regulates the restart of stalled replication forks following activation by the KHDC3L-OOEP scaffold complex (By similarity).ACTIVITY REGULATION Serine/threonine-protein kinase activity is directly stimulated by TOPBP1 (PubMed:16530042). ATR kinase activity is also directly activated by ETAA1, independently of TOPBP1 (PubMed:27723720, PubMed:27723717). Activated by DNA and inhibited by BCR-ABL oncogene (PubMed:10597277). Slightly activated by ATRIP (PubMed:14729973). Inhibited by caffeine, wortmannin and LY294002 (PubMed:9766667).SUBUNIT Forms a heterodimer with ATRIP.(PubMed:11721054). Binds to DNA, and to UV-damaged DNA with higher affinity. Interacts with RAD17, MSH2 and HDAC2. Present in a complex containing ATRIP and RPA-coated single-stranded DNA. Present in a complex containing CHD4 and HDAC2. Interacts with EEF1E1, the interaction is enhanced by UV irradiation. Interacts with CLSPN and CEP164. Interacts with TELO2 and TTI1. Interacts with BCR-ABL after genotoxic stress. Interacts with UHRF2; this interaction promotes ATR activation.TISSUE SPECIFICITY Ubiquitous, with highest expression in testis. Isoform 2 is found in pancreas, placenta and liver but not in heart, testis and ovary.PTM Phosphorylated; autophosphorylates in vitro.SIMILARITY Belongs to the PI3/PI4-kinase family. ATM subfamily. UniProt Q13535 1 EQUAL 2644 EQUAL Reactome Database ID Release 81 912443 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=912443 Reactome R-HSA-912443 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-912443.1 1 Reactome Database ID Release 81 176269 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=176269 Reactome R-HSA-176269 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-176269.1 ComplexPortal CPX-3622 Reactome Database ID Release 81 176203 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=176203 Reactome Database ID Release 81 176116 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=176116 Reactome R-HSA-176116 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-176116.2 12766152 Pubmed 2003 Human claspin is required for replication checkpoint control Chini, CC Chen, J J Biol Chem 278:30057-62 10859163 Pubmed 2000 Aberrant cell cycle checkpoint function and early embryonic death in Chk1(-/-) mice Takai, H Tominaga, K Motoyama, N Minamishima, YA Nagahama, H Tsukiyama, T Ikeda, K Nakayama, Keiko Nakanishi, M Nakayama, Ken-ichi Genes Dev 14:1439-47 10859164 Pubmed 2000 Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Liu, Q Guntuku, S Cui, XS Matsuoka, S Cortez, D Tamai, K Luo, G Carattini-Rivera, S DeMayo, F Bradley, A Donehower, LA Elledge, SJ Genes Dev 14:1448-59 15190204 Pubmed 2004 ATR, Claspin and the Rad9-Rad1-Hus1 complex regulate Chk1 and Cdc25A in the absence of DNA damage Sorensen, CS Syljuasen, RG Lukas, J Bartek, J Cell Cycle 3:941-5 15279789 Pubmed 2004 Chk1 in the DNA damage response: conserved roles from yeasts to mammals Chen, Y Sanchez, Y DNA Repair (Amst) 3:1025-32 11390642 Pubmed 2001 ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1 Zhao, H Piwnica-Worms, H Mol Cell Biol 21:4129-39 12781359 Pubmed 2003 Chk1 and Chk2 kinases in checkpoint control and cancer Bartek, J Lukas, J Cancer Cell 3:421-9 15272308 Pubmed 2004 Chk1, but not Chk2, inhibits Cdc25 phosphatases by a novel common mechanism Uto, K Inoue, D Shimuta, K Nakajo, N Sagata, N EMBO J 23:3386-96 16431910 Pubmed 2006 Rapid activation of ATR by ionizing radiation requires ATM and Mre11 Myers, JS Cortez, D J Biol Chem 16360315 Pubmed 2006 Rapid PIKK-Dependent Release of Chk1 from Chromatin Promotes the DNA-Damage Checkpoint Response Smits, VA Reaper, PM Jackson, SP Curr Biol 16:150-9 11090622 Pubmed 2000 Claspin, a novel protein required for the activation of Chk1 during a DNA replication checkpoint response in Xenopus egg extracts Kumagai, A Dunphy, WG Mol Cell 6:839-49 GENE ONTOLOGY GO:0006260 LEFT-TO-RIGHT CHEK2 is recruited to DNA DSBs CHEK2 (CHK2, Cds1) is recruited to DNA double-strand breaks (DSBs) mainly through its interaction with TP53BP1 (53BP1) (Wang et al. 2002), but BRCA1 also contributes to CHEK2 recruitment (Wilson and Stern 2008). Authored: Orlic-Milacic, Marija, 2015-05-12 Reviewed: Borowiec, James A, 2015-06-12 Edited: Orlic-Milacic, Marija, 2015-05-12 DNA DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1:p-4S,2T-BRCA1-A complex Reactome DB_ID: 5683605 p-4S,2T-BRCA1-A Complex p-S1387,S1423,S1524,S1547-BRCA1:p-T714,T734-BARD1:BRCC3:BRE:BABAM1:UIMC1:p-S406-FAM175A Reactome DB_ID: 5683606 NBA1 BABAM1 BRISC and BRCA1-A complex member 1 MERIT40 Reactome DB_ID: 5682582 UniProt:Q9NWV8 BABAM1 BABAM1 C19orf62 MERIT40 NBA1 HSPC142 FUNCTION Component of the BRCA1-A complex, a complex that specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). The BRCA1-A complex also possesses deubiquitinase activity that specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX. In the BRCA1-A complex, it is required for the complex integrity and its localization at DSBs. Component of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates (PubMed:24075985, PubMed:26195665). In these 2 complexes, it is probably required to maintain the stability of BABAM2 and help the 'Lys-63'-linked deubiquitinase activity mediated by BRCC3/BRCC36 component. The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1 (PubMed:26195665). Plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activity by enhancing its stability and cell surface expression (PubMed:24075985). Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination (PubMed:24075985).SUBUNIT Component of the ARISC complex, at least composed of UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:24075985). Component of the BRCA1-A complex, at least composed of BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:19261746, PubMed:19261749, PubMed:19261748, PubMed:21282113). In the BRCA1-A complex, interacts directly with ABRAXAS1 and BABAM2 (PubMed:19261749, PubMed:19261748). Component of the BRISC complex, at least composed of ABRAXAS2, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:19214193, PubMed:21282113, PubMed:24075985, PubMed:25283148). Identified in a complex with SHMT2 and the other subunits of the BRISC complex (PubMed:24075985).DOMAIN The VWFA-like region is similar to the VWFA domain. Its presence reveals similarities between the structure of the 19S proteasome and the BRCA1-A complexes.SIMILARITY Belongs to the BABAM1 family. UniProt Q9NWV8 1 EQUAL 329 EQUAL Reactome Database ID Release 81 5682582 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=5682582 Reactome R-HSA-5682582 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-5682582.1 1 UIMC1 BRCA1-A complex subunit RAP80 RAP80 Receptor-associated protein 80 RXRIP110 Retinoid X receptor-interacting protein 110 Ubiquitin interaction motif-containing protein 1 Reactome DB_ID: 5682574 UniProt:Q96RL1 UIMC1 UIMC1 RAP80 RXRIP110 FUNCTION Ubiquitin-binding protein (PubMed:24627472). Specifically recognizes and binds 'Lys-63'-linked ubiquitin (PubMed:19328070, Ref.38). Plays a central role in the BRCA1-A complex by specifically binding 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). The BRCA1-A complex also possesses deubiquitinase activity that specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX. Also weakly binds monoubiquitin but with much less affinity than 'Lys-63'-linked ubiquitin. May interact with monoubiquitinated histones H2A and H2B; the relevance of such results is however unclear in vivo. Does not bind Lys-48'-linked ubiquitin. May indirectly act as a transcriptional repressor by inhibiting the interaction of NR6A1 with the corepressor NCOR1.SUBUNIT Component of the ARISC complex, at least composed of UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:24075985). Component of the BRCA1-A complex, at least composed of the BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:17525341, PubMed:17525342, PubMed:19261746, PubMed:19261749). In the BRCA1-A complex, interacts directly with ABRAXAS1 (PubMed:17643121, PubMed:17643122, PubMed:19261749, PubMed:19261748, PubMed:18077395). Interacts with UBE2I (PubMed:17698038). Interacts with NR6A1 (PubMed:12080054). Interacts with ESR1 (PubMed:17311814). Interacts with TSP57 (By similarity). Interacts with TRAIP (PubMed:26781088).TISSUE SPECIFICITY Expressed in testis, ovary, thymus and heart. Expressed in germ cells of the testis.DOMAIN The tandem UIM domains form a continuous 60 Angstrom-long alpha-helix and mediate binding to 'Lys-63'-linked ubiquitins. UIM1 and UIM2 bind to the proximal and distal ubiquitin moieties and recognize an 'Ile-44'-centered hydrophobic patch. Since UIMs don't interact with the 'Lys-63' isopeptide bond the UIM-linker region between the 2 UIM domains determines the selectivity for 'Lys-63'-linkage, and its length is very important for specificity.DOMAIN The Abraxas-interacting region (AIR) mediates the interaction with ABRAXAS1.PTM Sumoylated.PTM Phosphorylated upon DNA damage by ATM or ATR.SIMILARITY Belongs to the RAP80 family. UniProt Q96RL1 1 EQUAL 719 EQUAL Reactome Database ID Release 81 5682574 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=5682574 Reactome R-HSA-5682574 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-5682574.1 1 BRE BRCC45 BRCA1-A complex subunit BRE Reactome DB_ID: 5682579 UniProt:Q9NXR7 BABAM2 BABAM2 BRE BRCC45 FUNCTION Component of the BRCA1-A complex, a complex that specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). The BRCA1-A complex also possesses deubiquitinase activity that specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX (PubMed:17525341, PubMed:19261746, PubMed:19261749, PubMed:19261748). In the BRCA1-A complex, it acts as an adapter that bridges the interaction between BABAM1/NBA1 and the rest of the complex, thereby being required for the complex integrity and modulating the E3 ubiquitin ligase activity of the BRCA1-BARD1 heterodimer (PubMed:21282113, PubMed:19261748). Component of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates (PubMed:19214193, PubMed:24075985, PubMed:25283148, PubMed:26195665). Within the BRISC complex, acts as an adapter that bridges the interaction between BABAM1/NBA1 and the rest of the complex, thereby being required for the complex integrity (PubMed:21282113). The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1 (PubMed:26195665). The BRISC complex plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activity by enhancing its stability and cell surface expression (PubMed:24075985). Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination (PubMed:24075985). May play a role in homeostasis or cellular differentiation in cells of neural, epithelial and germline origins. May also act as a death receptor-associated anti-apoptotic protein, which inhibits the mitochondrial apoptotic pathway. May regulate TNF-alpha signaling through its interactions with TNFRSF1A; however these effects may be indirect (PubMed:15465831).SUBUNIT Component of the ARISC complex, at least composed of UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:21282113, PubMed:24075985). Component of the BRCA1-A complex, at least composed of BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. In the BRCA1-A complex, interacts directly with ABRAXAS1, BRCC3/BRCC36 and BABAM1/NBA1. Binds polyubiquitin. Component of the BRISC complex, at least composed of ABRAXAS2, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:19214193, PubMed:21282113, PubMed:24075985, PubMed:25283148). Identified in a complex with SHMT2 and the other subunits of the BRISC complex (PubMed:24075985). Component of the BRCA1/BRCA2 containing complex (BRCC), which also contains BRCA1, BRCA2, BARD1, BRCC3/BRCC36 and RAD51. BRCC is a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage. May interact with FAS and TNFRSF1A (PubMed:15465831).TISSUE SPECIFICITY Expressed in all cell lines examined. Highly expressed in placenta.INDUCTION Down-regulated by DNA-damaging agents in fibroblasts, by retinoic acid in brain glioma U-251MG and promyelocytic HL-60 cell lines, and by bacterial lipopolysaccharides (LPS) in peripheral blood mononuclear cells (PBMC).DOMAIN Contains 2 ubiquitin-conjugating enzyme family-like (UEV-like) regions. These regions lack the critical Cys residues required for ubiquitination but retain the ability to bind ubiquitin.SIMILARITY Belongs to the BABAM2 family. UniProt Q9NXR7 1 EQUAL 383 EQUAL Reactome Database ID Release 81 5682579 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=5682579 Reactome R-HSA-5682579 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-5682579.1 1 Converted from EntitySet in Reactome p-S1387,S1423,S1524,S1547-BRCA1:p-T714,T734-BARD1 Reactome DB_ID: 9707287 K6PolyUb,p-5S-BRCA1:K6PolyUb,p-2T-BARD1 K6PolyUb,p-S988,S1387,S1423,S1524,S1547-BRCA1:K6PolyUb,p-T714,T734-BARD1 Reactome DB_ID: 9707288 K6PolyUb,p-T714,T734-BARD1 Reactome DB_ID: 9707286 UniProt:Q99728 BARD1 BARD1 FUNCTION E3 ubiquitin-protein ligase. The BRCA1-BARD1 heterodimer specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and coordinates a diverse range of cellular pathways such as DNA damage repair, ubiquitination and transcriptional regulation to maintain genomic stability. Plays a central role in the control of the cell cycle in response to DNA damage. Acts by mediating ubiquitin E3 ligase activity that is required for its tumor suppressor function. Also forms a heterodimer with CSTF1/CSTF-50 to modulate mRNA processing and RNAP II stability by inhibiting pre-mRNA 3' cleavage.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homo- and heterodimer. Heterodimer (RING-type zinc finger) with BRCA1. Heterodimer (via ANK repeats and BRCT domains) with CSTF1/CSTF-50. Component of the BRCA1-A complex, at least composed of the BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. Interacts with UBXN1.PTM Processed during apoptosis. The homodimer is more susceptible to proteolytic cleavage than the BARD1/BRCA1 heterodimer.CAUTION It is uncertain whether Met-1 or Met-26 is the initiator. UniProt Q99728 714 EQUAL 734 EQUAL 1 EQUAL 777 EQUAL Reactome Database ID Release 81 9707286 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=9707286 Reactome R-HSA-9707286 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-9707286.1 1 K6PolyUb,p-S1387,S1423,S1524,S1547-BRCA1 Reactome DB_ID: 9707290 UniProt:P38398 BRCA1 BRCA1 RNF53 FUNCTION E3 ubiquitin-protein ligase that specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage (PubMed:12890688, PubMed:14976165, PubMed:16818604, PubMed:17525340, PubMed:12887909, PubMed:10500182, PubMed:19261748). It is unclear whether it also mediates the formation of other types of polyubiquitin chains (PubMed:12890688). The BRCA1-BARD1 heterodimer coordinates a diverse range of cellular pathways such as DNA damage repair, ubiquitination and transcriptional regulation to maintain genomic stability (PubMed:12890688, PubMed:14976165, PubMed:20351172). Regulates centrosomal microtubule nucleation (PubMed:18056443). Required for appropriate cell cycle arrests after ionizing irradiation in both the S-phase and the G2 phase of the cell cycle (PubMed:10724175, PubMed:12183412, PubMed:11836499, PubMed:19261748). Required for FANCD2 targeting to sites of DNA damage (PubMed:12887909). Inhibits lipid synthesis by binding to inactive phosphorylated ACACA and preventing its dephosphorylation (PubMed:16326698). Contributes to homologous recombination repair (HRR) via its direct interaction with PALB2, fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks (PubMed:19369211). Component of the BRCA1-RBBP8 complex which regulates CHEK1 activation and controls cell cycle G2/M checkpoints on DNA damage via BRCA1-mediated ubiquitination of RBBP8 (PubMed:16818604). Acts as a transcriptional activator (PubMed:20160719).ACTIVITY REGULATION The E3 ubiquitin-protein ligase activity is inhibited by phosphorylation by AURKA. Activity is increased by phosphatase treatment.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Heterodimer with BARD1 (PubMed:11573085, PubMed:12890688, PubMed:14976165). Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the MRE11-RAD50-NBN protein (MRN) complex (PubMed:10783165). This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains (PubMed:10783165). Component of the BRCA1-A complex, at least composed of BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:19261746, PubMed:19261748, PubMed:19261749, PubMed:20351172). Interacts (via the BRCT domains) with ABRAXAS1 (phosphorylated form); this is important for recruitment to sites of DNA damage (PubMed:17525340, PubMed:17643121, PubMed:17643122, PubMed:24316840, PubMed:26778126, PubMed:23269703). Can form a heterotetramer with two molecules of ABRAXAS1 (phosphorylated form) (PubMed:26778126). Component of the BRCA1-RBBP8 complex (PubMed:16101277). Interacts (via the BRCT domains) with RBBP8 ('Ser-327' phosphorylated form); the interaction ubiquitinates RBBP8, regulates CHEK1 activation, and involves RBBP8 in BRCA1-dependent G2/M checkpoint control on DNA damage (PubMed:16818604, PubMed:9811458). Associates with RNA polymerase II holoenzyme (PubMed:9662397). Interacts with SMC1A, NELFB, DCLRE1C, CLSPN (PubMed:11877377, PubMed:15096610, PubMed:15456891, PubMed:11739404). Interacts with CHEK1, CHEK2, BAP1, BRCC3, UBXN1 and PCLAF (PubMed:10724175, PubMed:11836499, PubMed:14636569, PubMed:20351172, PubMed:21673012). Interacts (via BRCT domains) with BRIP1 (phosphorylated form) (PubMed:11301010, PubMed:15133502, PubMed:21473589). Interacts with FANCD2 (ubiquitinated form) (PubMed:11239454). Interacts with H2AX (phosphorylated on 'Ser-140') (PubMed:12419185). Interacts (via the BRCT domains) with ACACA (phosphorylated form); the interaction prevents dephosphorylation of ACACA (PubMed:12360400, PubMed:16326698, PubMed:16698035, PubMed:18452305). Part of a BRCA complex containing BRCA1, BRCA2 and PALB2 (PubMed:19369211). Interacts directly with PALB2; the interaction is essential for its function in HRR (PubMed:19369211, PubMed:28319063). Interacts directly with BRCA2; the interaction occurs only in the presence of PALB2 which serves as the bridging protein (PubMed:19369211). Interacts (via the BRCT domains) with LMO4; the interaction represses the transcriptional activity of BRCA1 (PubMed:11751867). Interacts (via the BRCT domains) with CCAR2 (via N-terminus); the interaction represses the transcriptional activator activity of BRCA1 (PubMed:20160719). Interacts with EXD2 (PubMed:26807646). Interacts (via C-terminus) with DHX9; this interaction is direct and links BRCA1 to the RNA polymerase II holoenzyme (PubMed:9662397).TISSUE SPECIFICITY Isoform 1 and isoform 3 are widely expressed. Isoform 3 is reduced or absent in several breast and ovarian cancer cell lines.DOMAIN The BRCT domains recognize and bind phosphorylated pSXXF motif on proteins. The interaction with the phosphorylated pSXXF motif of ABRAXAS1, recruits BRCA1 at DNA damage sites.DOMAIN The RING-type zinc finger domain interacts with BAP1.PTM Phosphorylated in response to IR, UV, and various stimuli that cause checkpoint activation, probably by ATM or ATR (PubMed:11114888, PubMed:12183412, PubMed:21144835). Phosphorylation at Ser-988 by CHEK2 regulates mitotic spindle assembly (PubMed:10724175, PubMed:20364141). Phosphorylation by AURKA regulates centrosomal microtubule nucleation (PubMed:18056443).PTM Autoubiquitinated, undergoes 'Lys-6'-linked polyubiquitination. 'Lys-6'-linked polyubiquitination does not promote degradation.POLYMORPHISM There is evidence that the presence of the rare form of Gln-356-Arg and Leu-871-Pro polymorphisms may be associated with an increased risk for developing ovarian cancer.CAUTION An article that concluded that AURKA-mediated phosphorylation of BRCA1 Ser-308 plays a role in the normal cell cycle G2/M transition was withdrawn due to data manipulation of flow cytometry data. UniProt P38398 1387 EQUAL 1423 EQUAL 1524 EQUAL 1547 EQUAL 1 EQUAL 1863 EQUAL Reactome Database ID Release 81 9707290 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=9707290 Reactome R-HSA-9707290 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-9707290.1 1 Reactome Database ID Release 81 9707288 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=9707288 Reactome R-HSA-9707288 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-9707288.1 p-S1387,S1423,S1524,S1547-BRCA1:p-T714,T734-BARD1 Reactome DB_ID: 5659852 phospho-BRCA1 p-S1387,S1423,S1524,S1547-BRCA1 Breast cancer type 1 susceptibility protein Reactome DB_ID: 75234 1 EQUAL 1863 EQUAL Reactome Database ID Release 81 75234 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=75234 Reactome R-HSA-75234 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-75234.1 1 p-T714,T734-BARD1 Reactome DB_ID: 5659846 1 EQUAL 777 EQUAL Reactome Database ID Release 81 5659846 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=5659846 Reactome R-HSA-5659846 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-5659846.1 1 Reactome Database ID Release 81 5659852 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=5659852 Reactome R-HSA-5659852 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-5659852.1 Reactome Database ID Release 81 9707287 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=9707287 Reactome R-HSA-9707287 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-9707287.1 1 BRCC3 Lys-63-specific deubiquitinase BRCC36 BRCC36 Reactome DB_ID: 5682577 UniProt:P46736 BRCC3 BRCC3 BRCC36 C6.1A CXorf53 FUNCTION Metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains (PubMed:19214193, PubMed:20656690, PubMed:24075985, PubMed:26344097). Does not have activity toward 'Lys-48'-linked polyubiquitin chains. Component of the BRCA1-A complex, a complex that specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks (DSBs). In the BRCA1-A complex, it specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX, antagonizing the RNF8-dependent ubiquitination at double-strand breaks (DSBs) (PubMed:20656690). Catalytic subunit of the BRISC complex, a multiprotein complex that specifically cleaves 'Lys-63'-linked ubiquitin in various substrates (PubMed:20656690, PubMed:24075985, PubMed:26344097, PubMed:26195665). Mediates the specific 'Lys-63'-specific deubiquitination associated with the COP9 signalosome complex (CSN), via the interaction of the BRISC complex with the CSN complex (PubMed:19214193). The BRISC complex is required for normal mitotic spindle assembly and microtubule attachment to kinetochores via its role in deubiquitinating NUMA1 (PubMed:26195665). Plays a role in interferon signaling via its role in the deubiquitination of the interferon receptor IFNAR1; deubiquitination increases IFNAR1 activity by enhancing its stability and cell surface expression (PubMed:24075985, PubMed:26344097). Down-regulates the response to bacterial lipopolysaccharide (LPS) via its role in IFNAR1 deubiquitination (PubMed:24075985). Deubiquitinates HDAC1 and PWWP2B leading to their stabilization (By similarity).SUBUNIT Component of the ARISC complex, at least composed of UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:20656690, PubMed:24075985). Component of the BRCA1-A complex, at least composed of BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, babam2 and BABAM1/NBA1. In the BRCA1-A complex, interacts directly with ABRAXAS1 and babam2 (PubMed:18077395, PubMed:19261748). Component of the BRISC complex, at least composed of ABRAXAS2, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:24075985, PubMed:25283148, PubMed:26344097). Identified in a complex with SHMT2 and the other subunits of the BRISC complex (PubMed:24075985). In the BRISC complex, interacts directly with ABRAXAS2 (PubMed:20656690, PubMed:26344097). Identified in a complex with ABRAXAS2 and NUMA1 (PubMed:26195665). The BRISC complex interacts with the CSN complex. Component of the BRCA1/BRCA2 containing complex (BRCC), which also contains BRCA1, BRCA2, BARD1, BABAM2 and RAD51. BRCC is a ubiquitin E3 ligase complex that enhances cellular survival following DNA damage. Interacts with BRCA1. Binds polyubiquitin. Interacts with PWWP2B (By similarity). Interacts with HDAC1; this interaction is enhanced in the presence of PWWP2B (By similarity).TISSUE SPECIFICITY Heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Aberrantly expressed in the vast majority of breast tumors.DISEASE A chromosomal aberration involving BRCC3 is a cause of pro-lymphocytic T-cell leukemia (T-PLL). Translocation t(X;14)(q28;q11) with TCRA.SIMILARITY Belongs to the peptidase M67A family. BRCC36 subfamily. UniProt P46736 2 EQUAL 316 EQUAL Reactome Database ID Release 81 5682577 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=5682577 Reactome R-HSA-5682577 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-5682577.1 1 p-S406-ABRA1 p-S406-FAM175A p-S406-Abraxas p-S406-CCDC98 Reactome DB_ID: 5682575 UniProt:Q6UWZ7 ABRAXAS1 ABRAXAS1 FAM175A ABRA1 CCDC98 UNQ496/PRO1013 FUNCTION Involved in DNA damage response and double-strand break (DSB) repair. Component of the BRCA1-A complex, acting as a central scaffold protein that assembles the various components of the complex and mediates the recruitment of BRCA1. The BRCA1-A complex specifically recognizes 'Lys-63'-linked ubiquitinated histones H2A and H2AX at DNA lesion sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at DSBs. This complex also possesses deubiquitinase activity that specifically removes 'Lys-63'-linked ubiquitin on histones H2A and H2AX.SUBUNIT Component of the ARISC complex, at least composed of UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:24075985). Component of the BRCA1-A complex, at least composed of BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1. In the complex, interacts directly with UIMC1/RAP80, BRCC3/BRCC36 and BABAM2. Interacts directly (when phosphorylated at Ser-406) with BRCA1. Homodimer. The homodimer interacts directly (when phosphorylated at Ser-404 and Ser-406) with two BRCA1 chains, giving rise to a heterotetramer. Binds polyubiquitin.PTM Phosphorylation of Ser-406 of the pSXXF motif by ATM or ATR constitutes a specific recognition motif for the BRCT domain of BRCA1 (PubMed:17643121, PubMed:17525340, PubMed:17643122). Ionizing radiation promotes rapid phosphorylation at Ser-404 and Ser-406 by ATM; this promotes recruitment of BRCA1 to sites of DNA damage (PubMed:26778126).SIMILARITY Belongs to the FAM175 family. Abraxas subfamily. UniProt Q6UWZ7 406 EQUAL 1 EQUAL 409 EQUAL Reactome Database ID Release 81 5682575 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=5682575 Reactome R-HSA-5682575 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-5682575.1 1 Reactome Database ID Release 81 5683606 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=5683606 Reactome R-HSA-5683606 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-5683606.2 1 DNA DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4:p-S25,S1778-TP53BP1 Reactome DB_ID: 5683417 DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1:RNF8:Zn2+:SUMO1:p-T4827-HERC2:UBE2N:UBE2V2:RNF168:PIAS4 Reactome DB_ID: 5683079 RNF168 E3 ubiquitin-protein ligase RNF168 RN168_HUMAN Reactome DB_ID: 4551605 UniProt:Q8IYW5 RNF168 RNF168 FUNCTION E3 ubiquitin-protein ligase required for accumulation of repair proteins to sites of DNA damage. Acts with UBE2N/UBC13 to amplify the RNF8-dependent histone ubiquitination. Recruited to sites of DNA damage at double-strand breaks (DSBs) by binding to ubiquitinated histone H2A and H2AX and amplifies the RNF8-dependent H2A ubiquitination, promoting the formation of 'Lys-63'-linked ubiquitin conjugates. This leads to concentrate ubiquitinated histones H2A and H2AX at DNA lesions to the threshold required for recruitment of TP53BP1 and BRCA1. Also recruited at DNA interstrand cross-links (ICLs) sites and promotes accumulation of 'Lys-63'-linked ubiquitination of histones H2A and H2AX, leading to recruitment of FAAP20/C1orf86 and Fanconi anemia (FA) complex, followed by interstrand cross-link repair. H2A ubiquitination also mediates the ATM-dependent transcriptional silencing at regions flanking DSBs in cis, a mechanism to avoid collision between transcription and repair intermediates. Also involved in class switch recombination in immune system, via its role in regulation of DSBs repair. Following DNA damage, promotes the ubiquitination and degradation of JMJD2A/KDM4A in collaboration with RNF8, leading to unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA damage sites. Not able to initiate 'Lys-63'-linked ubiquitination in vitro; possibly due to partial occlusion of the UBE2N/UBC13-binding region. Catalyzes monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub, respectively).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Monomer. Interacts with UBE2N/UBC13.DOMAIN The MIU motif (motif interacting with ubiquitin) mediates the interaction with both 'Lys-48'- and 'Lys-63'-linked ubiquitin chains (PubMed:19500350). The UMI motif mediates interaction with ubiquitin with a preference for 'Lys-63'-linked ubiquitin (PubMed:21041483). The specificity for different types of ubiquitin is mediated by juxtaposition of ubiquitin-binding motifs (MIU and UMI motifs) with LR motifs (LRMs) (PubMed:22742833).PTM Sumoylated with SUMO1 by PIAS4 in response to double-strand breaks (DSBs).PTM Ubiquitinated.SIMILARITY Belongs to the RNF168 family.CAUTION According to a well-established model, RNF168 cannot initiate H2A 'Lys-63'-linked ubiquitination and is recruited following RNF8-dependent histone ubiquitination to amplify H2A 'Lys-63'-linked ubiquitination (PubMed:19500350, PubMed:19203578 and PubMed:19203579). However, other data suggest that RNF168 is the priming ubiquitin ligase by mediating monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub respectively) (PubMed:22980979). These data suggest that RNF168 might be recruited to DSBs sites in a RNF8-dependent manner by binding to non-histone proteins ubiquitinated via 'Lys-63'-linked and initiates monoubiquitination of H2A, which is then amplified by RNF8 (PubMed:22980979). Additional evidence is however required to confirm these data. UniProt Q8IYW5 1 EQUAL 571 EQUAL Reactome Database ID Release 81 4551605 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=4551605 Reactome R-HSA-4551605 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-4551605.1 1 DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1:p-S102-WHSC1 Reactome DB_ID: 5682996 DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome:p-5T-MDC1 Reactome DB_ID: 5682997 p-5T-MDC1 p-5T-MDC1 homodimer Reactome DB_ID: 5682525 p-5T-MDC1 phospho-MDC1/NFBD1 Reactome DB_ID: 75236 UniProt:Q14676 MDC1 MDC1 KIAA0170 NFBD1 FUNCTION Required for checkpoint mediated cell cycle arrest in response to DNA damage within both the S phase and G2/M phases of the cell cycle. May serve as a scaffold for the recruitment of DNA repair and signal transduction proteins to discrete foci of DNA damage marked by 'Ser-139' phosphorylation of histone H2AX. Also required for downstream events subsequent to the recruitment of these proteins. These include phosphorylation and activation of the ATM, CHEK1 and CHEK2 kinases, and stabilization of TP53 and apoptosis. ATM and CHEK2 may also be activated independently by a parallel pathway mediated by TP53BP1.SUBUNIT Homodimer. Interacts with several proteins involved in the DNA damage response, although not all these interactions may be direct. Interacts with H2AX, which requires phosphorylation of H2AX on 'Ser-139'. Interacts with the MRN complex, composed of MRE11, RAD50, and NBN. Interacts with CHEK2, which requires ATM-mediated phosphorylation of 'Thr-68' within the FHA domain of CHEK2. Interacts constitutively with the BRCA1-BARD1 complex, SMC1A and TP53BP1. Interacts with ATM and FANCD2, and these interactions are reduced upon DNA damage. Also interacts with the PRKDC complex, composed of XRCC6/KU70, XRCC5/KU80 and PRKDC/XRCC7. This interaction may be required for PRKDC autophosphorylation, which is essential for DNA double strand break (DSB) repair. When phosphorylated by ATM, interacts with RNF8 (via FHA domain). Interacts with CEP164. When phosphorylated, interacts with APTX (via FHA-like domain).TISSUE SPECIFICITY Highly expressed in testis.DOMAIN Tandemly repeated BRCT domains are characteristic of proteins involved in DNA damage signaling. In MDC1, these repeats are required for localization to chromatin which flanks sites of DNA damage marked by 'Ser-139' phosphorylation of H2AX.PTM Phosphorylated upon exposure to ionizing radiation (IR), ultraviolet radiation (UV), and hydroxyurea (HU). Phosphorylation in response to IR requires ATM, NBN, and possibly CHEK2. Also phosphorylated during the G2/M phase of the cell cycle and during activation of the mitotic spindle checkpoint. Phosphorylation at Thr-4 by ATM stabilizes and enhances homodimerization via the FHA domain.PTM Sumoylation at Lys-1840 by PIAS4 following DNA damage promotes ubiquitin-mediated degradation.PTM Ubiquitinated by RNF4, leading to proteasomal degradation; undergoes 'Lys-48'-linked polyubiquitination. UniProt Q14676 4 EQUAL 699 EQUAL 719 EQUAL 752 EQUAL 765 EQUAL 1 EQUAL 2089 EQUAL Reactome Database ID Release 81 75236 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=75236 Reactome R-HSA-75236 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-75236.1 2 Reactome Database ID Release 81 5682525 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=5682525 Reactome R-HSA-5682525 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-5682525.1 1 DNA DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:K63PolyUb-K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome Reactome DB_ID: 5682995 DNA DSB:p-MRN:p-S1981,Ac-K3016-ATM:KAT5 Reactome DB_ID: 5682162 KAT5 Histone acetyltransferase KAT5 KAT5_HUMAN Tip60 Reactome DB_ID: 3321979 UniProt:Q92993 KAT5 KAT5 HTATIP TIP60 FUNCTION Catalytic subunit of the NuA4 histone acetyltransferase complex, a multiprotein complex involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H2A and H4 (PubMed:12776177, PubMed:15042092, PubMed:15121871, PubMed:15310756, PubMed:14966270, PubMed:16387653, PubMed:19909775, PubMed:25865756, PubMed:27153538, PubMed:29335245, PubMed:29174981, PubMed:33076429, PubMed:32822602). Histone acetylation alters nucleosome-DNA interactions and promotes interaction of the modified histones with other proteins which positively regulate transcription (PubMed:12776177, PubMed:15042092, PubMed:15121871, PubMed:15310756, PubMed:14966270). The NuA4 histone acetyltransferase complex is required for the activation of transcriptional programs associated with proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair (PubMed:17709392, PubMed:19783983, PubMed:32832608). The NuA4 complex plays a direct role in repair of DNA double-strand breaks (DSBs) by promoting homologous recombination (HR): the complex inhibits TP53BP1 binding to chromatin via MBTD1, which recognizes and binds histone H4 trimethylated at 'Lys-20' (H4K20me), and KAT5 that catalyzes acetylation of 'Lys-15' of histone H2A (H2AK15ac), thereby blocking the ubiquitination mark required for TP53BP1 localization at DNA breaks (PubMed:27153538, PubMed:32832608). Also involved in DSB repair by mediating acetylation of 'Lys-5' of histone H2AX (H2AXK5ac), promoting NBN/NBS1 assembly at the sites of DNA damage (PubMed:17709392, PubMed:26438602). The NuA4 complex plays a key role in hematopoietic stem cell maintenance and is required to maintain acetylated H2A.Z/H2AZ1 at MYC target genes (By similarity). The NuA4 complex is also required for spermatid development by promoting acetylation of histones: histone hyperacetylation is required for histone replacement during the transition from round to elongating spermatids (By similarity). Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome (PubMed:24463511). Also acetylates non-histone proteins, such as ARNTL/BMAL1, ATM, AURKB, CHKA, CGAS, ERCC4/XPF, LPIN1, NDC80/HEC1, NR1D2, RAN, SOX4, FOXP3, ULK1 and RUBCNL/Pacer (PubMed:16141325, PubMed:17360565, PubMed:17996965, PubMed:24835996, PubMed:26829474, PubMed:29040603, PubMed:30409912, PubMed:30704899, PubMed:32034146, PubMed:32817552, PubMed:34077757). Directly acetylates and activates ATM (PubMed:16141325). Promotes nucleotide excision repair (NER) by mediating acetylation of ERCC4/XPF, thereby promoting formation of the ERCC4-ERCC1 complex (PubMed:32034146). Relieves NR1D2-mediated inhibition of APOC3 expression by acetylating NR1D2 (PubMed:17996965). Acts as a regulator of regulatory T-cells (Treg) by catalyzing FOXP3 acetylation, thereby promoting FOXP3 transcriptional repressor activity (PubMed:17360565, PubMed:24835996). Involved in skeletal myoblast differentiation by mediating acetylation of SOX4 (PubMed:26291311). Catalyzes acetylation of APBB1/FE65, increasing its transcription activator activity (PubMed:33938178). Promotes transcription elongation during the activation phase of the circadian cycle by catalyzing acetylation of ARNTL/BMAL1, promoting elongation of circadian transcripts (By similarity). Together with GSK3 (GSK3A or GSK3B), acts as a regulator of autophagy: phosphorylated at Ser-86 by GSK3 under starvation conditions, leading to activate acetyltransferase activity and promote acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:30704899). Acts as a regulator of the cGAS-STING innate antiviral response by catalyzing acetylation the N-terminus of CGAS, thereby promoting CGAS DNA-binding and activation (PubMed:32817552). Also regulates lipid metabolism by mediating acetylation of CHKA or LPIN1 (PubMed:34077757). Promotes lipolysis of lipid droplets following glucose deprivation by mediating acetylation of isoform 1 of CHKA, thereby promoting monomerization of CHKA and its conversion into a tyrosine-protein kinase (PubMed:34077757). Acts as a regulator of fatty-acid-induced triacylglycerol synthesis by catalyzing acetylation of LPIN1, thereby promoting the synthesis of diacylglycerol (PubMed:29765047). In addition to protein acetyltransferase, can use different acyl-CoA substrates, such as (2E)-butenoyl-CoA (crotonyl-CoA) and 2-hydroxyisobutanoyl-CoA (2-hydroxyisobutyryl-CoA), and is able to mediate protein crotonylation and 2-hydroxyisobutyrylation, respectively (PubMed:29192674, PubMed:34608293). Acts as a key regulator of chromosome segregation and kinetochore-microtubule attachment during mitosis by mediating acetylation or crotonylation of target proteins (PubMed:26829474, PubMed:29040603, PubMed:30409912, PubMed:34608293). Catalyzes acetylation of AURKB at kinetochores, increasing AURKB activity and promoting accurate chromosome segregation in mitosis (PubMed:26829474). Acetylates RAN during mitosis, promoting microtubule assembly at mitotic chromosomes (PubMed:29040603). Acetylates NDC80/HEC1 during mitosis, promoting robust kinetochore-microtubule attachment (PubMed:30409912). Catalyzes crotonylation of MAPRE1/EB1, thereby ensuring accurate spindle positioning in mitosis (PubMed:34608293).ACTIVITY REGULATION Acyltransferase and acetyltransferase activities are activated by phosphorylation and autoacetylation (PubMed:20100829, PubMed:30704899). Autoacetylation activates the histone acetyltransferase activity (PubMed:20100829, PubMed:25865756, PubMed:30704899).SUBUNIT Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit KAT5/TIP60 and the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6 (PubMed:12963728, PubMed:10966108, PubMed:15196461, PubMed:14966270, PubMed:29174981). KAT5/TIP60, EPC1, and ING3 together constitute a minimal HAT complex termed Piccolo NuA4. The NuA4 complex interacts with MYC (PubMed:12776177). Interacts with ATM (PubMed:16141325). Interacts with JADE1 (PubMed:15502158). Interacts with PLA2G4A/CPLA2, EDNRA and HDAC7 (PubMed:11416127, PubMed:11262386, PubMed:12551922). Interacts with the cytoplasmic tail of APP and APBB1/FE65 (PubMed:33938178). Interacts with TRIM24 and TRIM68 (PubMed:18451177, PubMed:19909775). Forms a complex with SENP6 and UBE2I in response to UV irradiation. Identified in a complex with HINT1 (PubMed:16835243). Interacts with ATF2 and CUL3 (PubMed:18397884). Interacts with NR1D2 (via N-terminus) (PubMed:17996965). Component of a SWR1-like complex (PubMed:24463511). Interacts with FOXP3 (PubMed:17360565, PubMed:24835996). Interacts with ZBTB49 (PubMed:25245946). Interacts with SRF (By similarity). Interacts with ATF3; promoting autoacetylation and deubiquitination by USP7 (PubMed:25865756). Interacts with EP300/p300; interaction promotes KAT5 autoacetylation (PubMed:24835996). Interacts with PRKDC; interaction is impaired following KAT5 sumoylation (PubMed:32832608).SUBUNIT (Microbial infection) Interacts with HIV-1 TAT.PTM Phosphorylated on Ser-86 and Ser-90; enhanced during G2/M phase (PubMed:12468530, PubMed:26829474, PubMed:29335245). The phosphorylated form has a higher activity (PubMed:12468530, PubMed:29335245). Phosphorylation at Ser-90 by CDK1 or CDK9 is a prerequisite for phosphorylation at Ser-86 by GSK3 (PubMed:26829474, PubMed:30704899). Phosphorylation at Ser-86 by GSK3 (GSK3A or GSK3B) activates acetyltransferase and acyltransferase activities (PubMed:30704899). Phosphorylation at Ser-90 by CDK9 promotes KAT5 recruitment to chromatin (PubMed:29335245). Phosphorylation by VRK1 following DNA damage promotes KAT5 association with chromatin and histone acetyltransferase activity (PubMed:33076429).PTM Autoacetylated (PubMed:20100829, PubMed:24835996, PubMed:25301942, PubMed:26291311, PubMed:33938178). Autoacetylation is required for histone acetyltransferase activity (PubMed:20100829, PubMed:25865756). Autoacetylation at Lys-327 is facilitated by interaction with EP300/p300: it prevents ubiquitination and subsequent degradation by the proteasome and promotes acetylation of target proteins (PubMed:24835996). Deacetylated by HDAC3 and SIRT1 (PubMed:20100829, PubMed:25301942). Deacetylation by HDAC3 promotes its ubiquitination and cytoplasmic localization (PubMed:25301942).PTM Sumoylated by UBE2I at Lys-430 and Lys-451, leading to increase of its histone acetyltransferase activity in UV-induced DNA damage response, as well as its translocation to nuclear bodies (PubMed:17704809). Sumoylation with SUMO2 by PIAS4 at Lys-430 promotes repair of DNA double-strand breaks (DSBs) via homologous recombination (HR) (PubMed:32832608). Sumoylation by PIAS4 impairs interaction with PRKDC, inhibiting non-homologous end joining (NHEJ)-mediated repair of DSBs, thereby facilitating HR (PubMed:32832608). Desumoylated by SENP3 (PubMed:32832608).PTM Ubiquitinated by MDM2, leading to its proteasome-dependent degradation (PubMed:11927554, PubMed:24835996). Ubiquitination is prevented by autoacetylation at Lys-327 (PubMed:24835996). Ubiquitinated following deacetylation by HDAC3, leading to cytoplasmic localization (PubMed:25301942). Deubiquitinated by USP7 following interaction with ATF3, promoting its stabilization (PubMed:25865756).PTM (Microbial infection) In case of HIV-1 infection, interaction with the viral Tat protein leads to KAT5 polyubiquitination and targets it to degradation.SIMILARITY Belongs to the MYST (SAS/MOZ) family.CAUTION The role of the Tudor-knot domain, also named chromo barrel or chromodomain, is unclear. Based on its similarity with some chromo domains, it was first reported to bind histone H3 trimethylated on 'Lys-4' and/or 'Lys-9' (H3K4me3 and/or H3K9me3, respectively) (PubMed:19783983, PubMed:25560918). However, another group was not able to see any binding to methylated histones (PubMed:29494751). The 3D structure of the domain suggests that the inability to bind histones is caused by occlusion of the putative peptide-binding site by a basic amino acid side chain within a unique beta hairpin (PubMed:29494751). UniProt Q92993 1 EQUAL 513 EQUAL Reactome Database ID Release 81 3321979 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=3321979 Reactome R-HSA-3321979 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-3321979.1 1 1 DNA DSBs:p-MRN DNA DSBs:MRE11:RAD50:p-S343-NBN Reactome DB_ID: 5682175 p-MRN MRE11:RAD50:p-S343-NBN MRE11:RAD50:p-S343-NBS1 Reactome DB_ID: 5682166 RAD50 Reactome DB_ID: 75160 UniProt:Q92878 RAD50 RAD50 FUNCTION Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis. The complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11. RAD50 may be required to bind DNA ends and hold them in close proximity. This could facilitate searches for short or long regions of sequence homology in the recombining DNA templates, and may also stimulate the activity of DNA ligases and/or restrict the nuclease activity of MRE11 to prevent nucleolytic degradation past a given point (PubMed:11741547, PubMed:9590181, PubMed:9705271, PubMed:9651580). The complex may also be required for DNA damage signaling via activation of the ATM kinase (PubMed:15064416). In telomeres the MRN complex may modulate t-loop formation (PubMed:10888888).SUBUNIT Component of the MRN complex composed of two heterodimers RAD50/MRE11 associated with a single NBN (PubMed:8756642, PubMed:9590181, PubMed:9705271, PubMed:10839544, PubMed:26215093). As part of the MRN complex, interacts with MCM8 and MCM9; the interaction recruits the complex to DNA repair sites (PubMed:26215093). Component of the BASC complex, at least composed of BRCA1, MSH2, MSH6, MLH1, ATM, BLM, RAD50, MRE11 and NBN (PubMed:10783165). Found in a complex with TERF2 (PubMed:10888888). Interacts with RINT1 (PubMed:11096100). Interacts with BRCA1 via its N-terminal domain (PubMed:10426999). Interacts with DCLRE1C/Artemis (PubMed:15456891, PubMed:15723659). Interacts with MRNIP (PubMed:27568553). Interacts with CYREN (via XLF motif) (By similarity).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein UL12 (PubMed:20943970).TISSUE SPECIFICITY Expressed at very low level in most tissues, except in testis where it is expressed at higher level. Expressed in fibroblasts.DOMAIN The zinc-hook, which separates the large intramolecular coiled coil regions, contains 2 Cys residues that coordinate one molecule of zinc with the help of the 2 Cys residues of the zinc-hook of another RAD50 molecule, thereby forming a V-shaped homodimer. The two heads of the homodimer, which constitute the ATP-binding domain, interact with the MRE11 homodimer (By similarity).MISCELLANEOUS In case of infection by adenovirus E4, the MRN complex is inactivated and degraded by viral oncoproteins, thereby preventing concatenation of viral genomes in infected cells.SIMILARITY Belongs to the SMC family. RAD50 subfamily. UniProt Q92878 1 EQUAL 1312 EQUAL Reactome Database ID Release 81 75160 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=75160 Reactome R-HSA-75160 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-75160.1 1 p-S343-NBN phospho-NBS1 Reactome DB_ID: 75237 UniProt:O60934 NBN NBN NBS NBS1 P95 FUNCTION Component of the MRE11-RAD50-NBN (MRN complex) which plays a critical role in the cellular response to DNA damage and the maintenance of chromosome integrity. The complex is involved in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity, cell cycle checkpoint control and meiosis. The complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11. RAD50 may be required to bind DNA ends and hold them in close proximity. NBN modulate the DNA damage signal sensing by recruiting PI3/PI4-kinase family members ATM, ATR, and probably DNA-PKcs to the DNA damage sites and activating their functions. It can also recruit MRE11 and RAD50 to the proximity of DSBs by an interaction with the histone H2AX. NBN also functions in telomere length maintenance by generating the 3' overhang which serves as a primer for telomerase dependent telomere elongation. NBN is a major player in the control of intra-S-phase checkpoint and there is some evidence that NBN is involved in G1 and G2 checkpoints. The roles of NBS1/MRN encompass DNA damage sensor, signal transducer, and effector, which enable cells to maintain DNA integrity and genomic stability. Forms a complex with RBBP8 to link DNA double-strand break sensing to resection. Enhances AKT1 phosphorylation possibly by association with the mTORC2 complex.SUBUNIT Component of the MRN complex composed of two heterodimers RAD50/MRE11 associated with a single NBN (PubMed:26215093, PubMed:9590181, PubMed:9705271, PubMed:11238951). As part of the MRN complex, interacts with MCM9; the interaction recruits the complex to DNA repair sites (PubMed:26215093). Component of the BASC complex, at least composed of BRCA1, MSH2, MSH6, MLH1, ATM, BLM, RAD50, MRE11 and NBN (PubMed:10783165). Interacts with histone H2AX this requires phosphorylation of H2AX on 'Ser-139' (PubMed:12419185). Interacts with HJURP (PubMed:17823411). Interacts with INTS3 (PubMed:19683501). Interacts with KPNA2 (PubMed:16188882). Interacts with TERF2 (PubMed:10888888). Interacts with RBBP8; the interaction links the role of the MRN complex in DNA double-strand break sensing to resection (PubMed:19759395). Interacts with SP100; recruits NBN to PML bodies (PubMed:12470659). Interacts with ATF2 (PubMed:15916964). Interacts with MTOR, MAPKAP1 isoform 2 and RICTOR; indicative for an association with the mTORC2 complex (PubMed:23762398). Interacts with MRNIP (PubMed:27568553). Interacts with UFL1; promoting UFL1 recruitment to double-strand breaks following DNA damage (PubMed:30886146). Interacts with CYREN (via XLF motif) (By similarity).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein UL12.TISSUE SPECIFICITY Ubiquitous (PubMed:9590180). Expressed at high levels in testis (PubMed:9590180).INDUCTION Up-regulated by ionizing radiation (IR).DOMAIN The FHA and BRCT domains are likely to have a crucial role for both binding to histone H2AX and for relocalization of MRE11/RAD50 complex to the vicinity of DNA damage.DOMAIN The C-terminal domain contains a MRE11-binding site, and this interaction is required for the nuclear localization of the MRN complex.DOMAIN The EEXXXDDL motif at the C-terminus is required for the interaction with ATM and its recruitment to sites of DNA damage and promote the phosphorylation of ATM substrates, leading to the events of DNA damage response.PTM Phosphorylated by ATM in response of ionizing radiation, and such phosphorylation is responsible intra-S phase checkpoint control and telomere maintenance.DISEASE Defects in NBN might play a role in the pathogenesis of childhood acute lymphoblastic leukemia (ALL).MISCELLANEOUS In case of infection by adenovirus E4, the MRN complex is inactivated and degraded by viral oncoproteins, thereby preventing concatenation of viral genomes in infected cells. UniProt O60934 343 EQUAL 1 EQUAL 754 EQUAL Reactome Database ID Release 81 75237 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=75237 Reactome R-HSA-75237 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-75237.1 1 MRE11A Double-strand break repair protein MRE11A MRE11 homolog 1 Reactome DB_ID: 59544 UniProt:P49959 MRE11 MRE11 HNGS1 MRE11A FUNCTION Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:11741547, PubMed:29670289). The complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11 (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:11741547, PubMed:29670289). RAD50 may be required to bind DNA ends and hold them in close proximity (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:11741547, PubMed:29670289). This could facilitate searches for short or long regions of sequence homology in the recombining DNA templates, and may also stimulate the activity of DNA ligases and/or restrict the nuclease activity of MRE11 to prevent nucleolytic degradation past a given point (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:11741547, PubMed:29670289, PubMed:30612738). The complex may also be required for DNA damage signaling via activation of the ATM kinase (PubMed:15064416). In telomeres the MRN complex may modulate t-loop formation (PubMed:10888888).ACTIVITY REGULATION Interaction with SAMHD1 stimulates the double-strand-specific 3'-5' exonuclease activity.SUBUNIT Component of the MRN complex composed of two heterodimers RAD50/MRE11 associated with a single NBN (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:10839544, PubMed:26215093). As part of the MRN complex, interacts with MCM9; the interaction recruits the complex to DNA repair sites (PubMed:26215093). Component of the BASC complex, at least composed of BRCA1, MSH2, MSH6, MLH1, ATM, BLM, RAD50, MRE11 and NBN (PubMed:10783165). Found in a complex with TERF2 (PubMed:10888888). Interacts with DCLRE1C/Artemis and DCLRE1B/Apollo (PubMed:15456891, PubMed:15723659, PubMed:18469862). Interacts with ATF2 (PubMed:15916964). Interacts with EXD2 (PubMed:26807646). Interacts with MRNIP (PubMed:27568553). Interacts with SAMHD1; leading to stimulate 3'-5' exonuclease activity (PubMed:28834754, PubMed:29670289). Interacts (when ubiquitinated) with UBQLN4 (via its UBA domain) (PubMed:30612738). Interacts with CYREN (via XLF motif) (By similarity).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein UL12 (PubMed:20943970).PTM Ubiquitinated following DNA damage. Ubiquitination triggers interaction with UBQLN4, leading to MRE11 removal from chromatin and degradation by the proteasome.DISEASE Defects in MRE11 can be a cause of nephronophthisis-related ciliopathies (NPHP-RC), a group of recessive diseases that affect kidney, retina and brain. A homozygous truncating mutation MRE11 has been found in patients with cerebellar vermis hypoplasia, ataxia and dysarthria.MISCELLANEOUS In case of infection by adenovirus E4, the MRN complex is inactivated and degraded by viral oncoproteins, thereby preventing concatenation of viral genomes in infected cells.SIMILARITY Belongs to the MRE11/RAD32 family. UniProt P49959 1 EQUAL 708 EQUAL Reactome Database ID Release 81 59544 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=59544 Reactome R-HSA-59544 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-59544.1 1 Reactome Database ID Release 81 5682166 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=5682166 Reactome R-HSA-5682166 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-5682166.1 ComplexPortal CPX-4442 1 DNA double-strand break ends Reactome DB_ID: 75165 Reactome Database ID Release 81 75165 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=75165 Reactome R-ALL-75165 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-75165.2 ChEBI 61120 1 Reactome Database ID Release 81 5682175 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=5682175 Reactome R-HSA-5682175 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-5682175.1 ComplexPortal CPX-4442 1 Reactome Database ID Release 81 5682162 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=5682162 Reactome R-HSA-5682162 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-5682162.1 1 K63PolyUb:K14,K16,p-S139-H2AFX,Me2K21-HIST1H4A-Nucleosome Nucleosome with Histone K63PolyUb,gamma-H2A.x and H4K20Me2 Reactome DB_ID: 5682998 Ub,gamma-H2AX K63PolyUb-K14,K16,p-S140-H2AFX K63PolyUb-K14,K16,p-S139-H2AFX Reactome DB_ID: 5682847 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). Interacts with HDGFL2 (PubMed:26721387).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-6 (H2AXK5ac) by KAT5 component of the NuA4 histone acetyltransferase complex promotes NBN/NBS1 assembly at the sites of DNA damage (PubMed:17709392, PubMed:26438602). 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 140 EQUAL 14 EQUAL 16 EQUAL 2 EQUAL 143 EQUAL Reactome Database ID Release 81 5682847 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=5682847 Reactome R-HSA-5682847 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-5682847.2 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 81 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 81 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 81 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 81 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 81 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 81 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 81 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 81 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 81 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 81 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 re