BioPAX pathway converted from "CDK12 phosphorylates RNA Pol II CTD at DNA repair genes" in the Reactome database.

2.7.11.22

CDK12 phosphorylates RNA Pol II CTD at DNA repair genes

CDK12, in complex with CCNK (cyclin K), phosphorylates heptapeptide repeats in the C-terminal domain (CTD) of the RNA polymerase II (RNA Pol II) subunit POLR2A. CDK12 may require phosphorylation of its threonine residue T893 to achieve full catalytic activity, but the activating kinase is not known. CDK12-mediated phosphorylation of the CTD of POLR2A occurs after the heptapeptide repeats in the CTD of POLR2A undergo phosphorylation by the CDK9-containing P-TEFb complex. It is unclear whether CDK12 acts on the second serine or the fifth serine or both in the YSPTSPS repeats. The mammalian POLR2A contains 52 heptapeptide repeats that start at amino acid position 1615. The exact localization of CDK9 and CDK12 target sites relative to the full-length POLR2A is not known. CDK12-mediated phosphorylation of the pre-phosphorylated RNA Pol II complex is important for the transcription of a group of genes with long and complex structures, involved in DNA repair (Blazek et al. 2011, Cheng et al. 2012, Bosken et al. 2014, Bartkowiak and Greenleaf 2015, Liang et al. 2015).

Authored: Orlic-Milacic, Marija, 2015-10-14Reviewed: Zaccara, Sara, 2016-02-04Reviewed: Inga, Alberto, 2016-02-04Edited: Orlic-Milacic, Marija, 2015-10-14

Reactome DB_ID: 6797614

nucleoplasmGO0005654CCNK:CDK12:Elongation Complex at DNA Repair Genes [nucleoplasm]

CCNK:CDK12:Elongation Complex at DNA Repair Genes

Reactome DB_ID: 6797611

Elongation Complex at DNA Repair Genes [nucleoplasm]

Elongation Complex at DNA Repair Genes

Reactome DB_ID: 109634

TFIIH [nucleoplasm]

TFIIH

Reactome DB_ID: 67439

UniProt:P19447 ERCC3

ERCC3

XPBCERCC3XPBFUNCTION ATP-dependent 3'-5' DNA helicase, component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. The ATPase activity of XPB/ERCC3, but not its helicase activity, is required for DNA opening. In transcription, TFIIH has an essential role in transcription initiation (PubMed:8157004, PubMed:30894545). When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape (PubMed:8157004). The ATP-dependent helicase activity of XPB/ERCC3 is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription.SUBUNIT Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK-activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription (PubMed:9852112). Interacts with PUF60 (PubMed:10882074, PubMed:11239393). Interacts with ATF7IP (PubMed:19106100). Interacts with KAT2A; leading to KAT2A recruitment to promoters and acetylation of histones (PubMed:30894545).SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus EBNA2.SIMILARITY Belongs to the helicase family. RAD25/XPB subfamily.

Reactomehttp://www.reactome.orgHomo sapiens

NCBI Taxonomy9606UniProtP19447

Chain Coordinates

EQUAL

782

EQUAL

Reactome DB_ID: 65916

UniProt:Q13889 GTF2H3

GTF2H3

GTF2H3FUNCTION Component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. In transcription, TFIIH has an essential role in transcription initiation. When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription.SUBUNIT Part of a TFIID-containing RNA polymerase II pre-initiation complex that is composed of TBP and at least GTF2A1, GTF2A2, GTF2E1, GTF2E2, GTF2F1, GTF2H2, GTF2H3, GTF2H4, GTF2H5, GTF2B, TCEA1, ERCC2, ERCC3, TAF1, TAF2, TAF3, TAF4, TAF5, TAF6, TAF7, TAF8, TAF9, TAF10, TAF11, TAF12 and TAF13 (PubMed:27193682). Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK-activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription (PubMed:9852112). Interacts with RARA; the interaction requires prior phosphorylation of RARA on 'Ser-369' which then enhances interaction of RARA with CDK7 (By similarity).SIMILARITY Belongs to the TFB4 family.

UniProtQ13889

EQUAL

308

EQUAL

Reactome DB_ID: 65912

UniProt:P32780 GTF2H1

GTF2H1

BTF2GTF2H1FUNCTION Component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. In transcription, TFIIH has an essential role in transcription initiation. When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription.SUBUNIT Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK-activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription. Interacts with PUF60.SIMILARITY Belongs to the TFB1 family.

UniProtP32780

EQUAL

548

EQUAL

Reactome DB_ID: 69221

CAK [nucleoplasm]

CAK

Reactome DB_ID: 69218

UniProt:P50613 CDK7

CDK7

STK1CDK7MO15CDKN7CAK1CAKFUNCTION Serine/threonine kinase involved in cell cycle control and in RNA polymerase II-mediated RNA transcription. Cyclin-dependent kinases (CDKs) are activated by the binding to a cyclin and mediate the progression through the cell cycle. Each different complex controls a specific transition between 2 subsequent phases in the cell cycle. Required for both activation and complex formation of CDK1/cyclin-B during G2-M transition, and for activation of CDK2/cyclins during G1-S transition (but not complex formation). CDK7 is the catalytic subunit of the CDK-activating kinase (CAK) complex. Phosphorylates SPT5/SUPT5H, SF1/NR5A1, POLR2A, p53/TP53, CDK1, CDK2, CDK4, CDK6 and CDK11B/CDK11. CAK activates the cyclin-associated kinases CDK1, CDK2, CDK4 and CDK6 by threonine phosphorylation, thus regulating cell cycle progression. CAK complexed to the core-TFIIH basal transcription factor activates RNA polymerase II by serine phosphorylation of the repetitive C-terminal domain (CTD) of its large subunit (POLR2A), allowing its escape from the promoter and elongation of the transcripts. Phosphorylation of POLR2A in complex with DNA promotes transcription initiation by triggering dissociation from DNA. Its expression and activity are constant throughout the cell cycle. Upon DNA damage, triggers p53/TP53 activation by phosphorylation, but is inactivated in turn by p53/TP53; this feedback loop may lead to an arrest of the cell cycle and of the transcription, helping in cell recovery, or to apoptosis. Required for DNA-bound peptides-mediated transcription and cellular growth inhibition.ACTIVITY REGULATION Inactivated by phosphorylation. Repressed by roscovitine (seliciclib, CYC202), R547 (Ro-4584820) and SNS-032 (BMS-387032). The association of p53/TP53 to the CAK complex in response to DNA damage reduces kinase activity toward CDK2 and RNA polymerase II repetitive C-terminal domain (CTD), thus stopping cell cycle progression. The inactivation by roscovitine promotes caspase-mediated apoptosis in leukemic cells.SUBUNIT Associates primarily with cyclin-H (CCNH) and MAT1 to form the CAK complex. CAK can further associate with the core-TFIIH to form the TFIIH basal transcription factor; this complex is sensitive to UV light. The CAK complex binds to p53/TP53 in response to DNA damage. Interacts with CDK2, SF1/NR5A1, PUF60 and PRKCI.TISSUE SPECIFICITY Ubiquitous.INDUCTION Repressed by DNA-bound peptides.PTM Phosphorylation of Ser-164 during mitosis inactivates the enzyme. Phosphorylation of Thr-170 is required for activity. Phosphorylated at Ser-164 and Thr-170 by CDK2.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.

UniProtP50613

EQUAL

346

EQUAL

Reactome DB_ID: 59012

UniProt:P51948 MNAT1

MNAT1

MAT1RNF66CAP35MNAT1FUNCTION Stabilizes the cyclin H-CDK7 complex to form a functional CDK-activating kinase (CAK) enzymatic complex. CAK activates the cyclin-associated kinases CDK1, CDK2, CDK4 and CDK6 by threonine phosphorylation. CAK complexed to the core-TFIIH basal transcription factor activates RNA polymerase II by serine phosphorylation of the repetitive C-terminal domain (CTD) of its large subunit (POLR2A), allowing its escape from the promoter and elongation of the transcripts. Involved in cell cycle control and in RNA transcription by RNA polymerase II.SUBUNIT Associates primarily with CDK7 and cyclin H to form the CAK complex. CAK can further associate with the core-TFIIH to form the TFIIH basal transcription factor.TISSUE SPECIFICITY Highest levels in colon and testis. Moderate levels are present thymus, prostate, ovary, and small intestine. The lowest levels are found in spleen and leukocytes.

UniProtP51948

EQUAL

309

EQUAL

Reactome DB_ID: 69220

UniProt:P51946 CCNH

CCNH

CCNHFUNCTION Regulates CDK7, the catalytic subunit of the CDK-activating kinase (CAK) enzymatic complex. CAK activates the cyclin-associated kinases CDK1, CDK2, CDK4 and CDK6 by threonine phosphorylation. CAK complexed to the core-TFIIH basal transcription factor activates RNA polymerase II by serine phosphorylation of the repetitive C-terminal domain (CTD) of its large subunit (POLR2A), allowing its escape from the promoter and elongation of the transcripts. Involved in cell cycle control and in RNA transcription by RNA polymerase II. Its expression and activity are constant throughout the cell cycle.SUBUNIT Associates primarily with CDK7 and MAT1 to form the CAK complex. CAK can further associate with the core-TFIIH to form the TFIIH basal transcription factor.SIMILARITY Belongs to the cyclin family. Cyclin C subfamily.

UniProtP51946

EQUAL

323

EQUAL

Reactome Database ID Release 7569221Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=69221ReactomeR-HSA-69221

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-69221.1

Reactome DB_ID: 5688446

UniProt:Q6ZYL4 GTF2H5

GTF2H5

C6orf175TTDAGTF2H5FUNCTION Component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. In transcription, TFIIH has an essential role in transcription initiation. When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription. Necessary for the stability of the TFIIH complex and for the presence of normal levels of TFIIH in the cell.SUBUNIT Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK-activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription.SIMILARITY Belongs to the TFB5 family.

UniProtQ6ZYL4

EQUAL

Reactome DB_ID: 65918

UniProt:Q92759 GTF2H4

GTF2H4

GTF2H4FUNCTION Component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. In transcription, TFIIH has an essential role in transcription initiation. When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription.SUBUNIT Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK-activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription.SIMILARITY Belongs to the TFB2 family.

UniProtQ92759

EQUAL

462

EQUAL

Reactome DB_ID: 65914

UniProt:Q13888 GTF2H2

GTF2H2

BTF2P44GTF2H2FUNCTION Component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. In transcription, TFIIH has an essential role in transcription initiation. When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription. The N-terminus of GTF2H2 interacts with and regulates XPD whereas an intact C-terminus is required for a successful escape of RNAP II form the promoter.SUBUNIT Component of the TFIID-containing RNA polymerase II pre-initiation complex that is composed of TBP and at least GTF2A1, GTF2A2, GTF2E1, GTF2E2, GTF2F1, GTF2H2, GTF2H3, GTF2H4, GTF2H5, GTF2B, TCEA1, ERCC2 and ERCC3 (PubMed:27193682). Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK-activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription (PubMed:9852112, PubMed:11319235). Interacts with XPB, XPD, GTF2H1 and GTF2H3 (PubMed:11319235).SUBUNIT (Microbial infection) Interacts with varicella-zoster virus IE63 protein.TISSUE SPECIFICITY Widely expressed, with higher expression in skeletal muscle.SIMILARITY Belongs to the GTF2H2 family.

UniProtQ13888

EQUAL

395

EQUAL

Reactome DB_ID: 67443

UniProt:P18074 ERCC2

ERCC2

ERCC2XPDXPDCFUNCTION ATP-dependent 5'-3' DNA helicase, component of the general transcription and DNA repair factor IIH (TFIIH) core complex, which is involved in general and transcription-coupled nucleotide excision repair (NER) of damaged DNA and, when complexed to CAK, in RNA transcription by RNA polymerase II. In NER, TFIIH acts by opening DNA around the lesion to allow the excision of the damaged oligonucleotide and its replacement by a new DNA fragment. The ATP-dependent helicase activity of XPD/ERCC2 is required for DNA opening. In transcription, TFIIH has an essential role in transcription initiation. When the pre-initiation complex (PIC) has been established, TFIIH is required for promoter opening and promoter escape. Phosphorylation of the C-terminal tail (CTD) of the largest subunit of RNA polymerase II by the kinase module CAK controls the initiation of transcription. XPD/ERCC2 acts by forming a bridge between CAK and the core-TFIIH complex. Involved in the regulation of vitamin-D receptor activity. As part of the mitotic spindle-associated MMXD complex it plays a role in chromosome segregation. Might have a role in aging process and could play a causative role in the generation of skin cancers.SUBUNIT Component of the 7-subunit TFIIH core complex composed of XPB/ERCC3, XPD/ERCC2, GTF2H1, GTF2H2, GTF2H3, GTF2H4 and GTF2H5, which is active in NER. The core complex associates with the 3-subunit CDK-activating kinase (CAK) module composed of CCNH/cyclin H, CDK7 and MNAT1 to form the 10-subunit holoenzyme (holo-TFIIH) active in transcription. The interaction with GTF2H2 results in the stimulation of the 5'-->3' helicase activity (PubMed:9771713, PubMed:9852112). Component of the MMXD complex, which includes CIAO1, ERCC2, CIAO2B, MMS19 and SLC25A5 (PubMed:20797633). Interacts with CIAO1 and CIAO2B; the interaction WITH CIAO2B is direct (PubMed:23891004). Interacts with ATF7IP (PubMed:19106100). Interacts directly with MMS19 (PubMed:23585563).SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus EBNA2.PTM ISGylated.SIMILARITY Belongs to the helicase family. RAD3/XPD subfamily.

UniProtP18074

EQUAL

760

EQUAL

Reactome Database ID Release 75109634Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=109634ReactomeR-HSA-109634

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-109634.1

Reactome DB_ID: 6797609

Hyperphosphorylated RNA Pol II at DNA repair genes [nucleoplasm]

Hyperphosphorylated RNA Pol II at DNA repair genes

Converted from EntitySet in Reactome

Reactome DB_ID: 6797615

DNA repair genes regulated by CDK12 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityATR Gene [nucleoplasm]BRCA1 gene [nucleoplasm]FANCI Gene [nucleoplasm]FANCD2 Gene [nucleoplasm]

ENSEMBLENSG00000175054ENSEMBLENSG00000012048ENSEMBLENSG00000140525ENSEMBLENSG00000144554

Reactome DB_ID: 112431

P-TEFb complex [nucleoplasm]

P-TEFb complex

Reactome DB_ID: 51801

UniProt:P50750 CDK9

CDK9

CDK9CDC2L4TAKFUNCTION Protein kinase involved in the regulation of transcription (PubMed:10574912, PubMed:10757782, PubMed:11145967, PubMed:11575923, PubMed:11809800, PubMed:11884399, PubMed:14701750, PubMed:16109376, PubMed:16109377, PubMed:20930849, PubMed:28426094). Member of the cyclin-dependent kinase pair (CDK9/cyclin-T) complex, also called positive transcription elongation factor b (P-TEFb), which facilitates the transition from abortive to productive elongation by phosphorylating the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAP II) POLR2A, SUPT5H and RDBP (PubMed:10574912, PubMed:10757782, PubMed:11145967, PubMed:11575923, PubMed:11809800, PubMed:11884399, PubMed:14701750, PubMed:16109376, PubMed:16109377, PubMed:20930849, PubMed:28426094). This complex is inactive when in the 7SK snRNP complex form (PubMed:10574912, PubMed:10757782, PubMed:11145967, PubMed:11575923, PubMed:11809800, PubMed:11884399, PubMed:14701750, PubMed:16109376, PubMed:16109377, PubMed:20930849, PubMed:28426094). Phosphorylates EP300, MYOD1, RPB1/POLR2A and AR and the negative elongation factors DSIF and NELF (PubMed:9857195, PubMed:10912001, PubMed:11112772, PubMed:12037670, PubMed:20081228, PubMed:20980437, PubMed:21127351). Regulates cytokine inducible transcription networks by facilitating promoter recognition of target transcription factors (e.g. TNF-inducible RELA/p65 activation and IL-6-inducible STAT3 signaling) (PubMed:17956865, PubMed:18362169). Promotes RNA synthesis in genetic programs for cell growth, differentiation and viral pathogenesis (PubMed:10393184, PubMed:11112772). P-TEFb is also involved in cotranscriptional histone modification, mRNA processing and mRNA export (PubMed:15564463, PubMed:19575011, PubMed:19844166). Modulates a complex network of chromatin modifications including histone H2B monoubiquitination (H2Bub1), H3 lysine 4 trimethylation (H3K4me3) and H3K36me3; integrates phosphorylation during transcription with chromatin modifications to control co-transcriptional histone mRNA processing (PubMed:15564463, PubMed:19575011, PubMed:19844166). The CDK9/cyclin-K complex has also a kinase activity towards CTD of RNAP II and can substitute for CDK9/cyclin-T P-TEFb in vitro (PubMed:21127351). Replication stress response protein; the CDK9/cyclin-K complex is required for genome integrity maintenance, by promoting cell cycle recovery from replication arrest and limiting single-stranded DNA amount in response to replication stress, thus reducing the breakdown of stalled replication forks and avoiding DNA damage (PubMed:20493174). In addition, probable function in DNA repair of isoform 2 via interaction with KU70/XRCC6 (PubMed:20493174). Promotes cardiac myocyte enlargement (PubMed:20081228). RPB1/POLR2A phosphorylation on 'Ser-2' in CTD activates transcription (PubMed:21127351). AR phosphorylation modulates AR transcription factor promoter selectivity and cell growth. DSIF and NELF phosphorylation promotes transcription by inhibiting their negative effect (PubMed:9857195, PubMed:10912001, PubMed:11112772). The phosphorylation of MYOD1 enhances its transcriptional activity and thus promotes muscle differentiation (PubMed:12037670).ACTIVITY REGULATION Inhibited by CDKI-71, CR8, GPC-286199, AG-024322, flavopiridol (alvocidib), RBG-286147, anilinopyrimidine 32, arylazopyrazole 31b, indirubin 3'-monoxime, meriolin 3,P276-00, olomoucine II, pyrazolotriazine, meriolin, variolin, thiazolyl-pyrimidine, thiazolyl-pyrimidine, indirubin-30-monoxime, ZK 304709, AG-012986, AT7519, R547, RGB-286638, imidazole pyrimidine, EXEL-3700, EXEL-8647, 5,6-dichloro-1-b-ribofur-anosyl-benzimidazole (DRB), P276-00, roscovitine (seliciclib, CYC202) and SNS-032 (BMS-387032). Activation by Thr-186 phosphorylation is calcium Ca(2+) signaling pathway-dependent; actively inactivated by dephosphorylation mediated by PPP1CA, PPM1A and PPM1B. Reversibly repressed by acetylation at Lys-44 and Lys-48.SUBUNIT Component of the super elongation complex (SEC), at least composed of EAF1, EAF2, CDK9, MLLT3/AF9, AFF (AFF1 or AFF4), the P-TEFb complex and ELL (ELL, ELL2 or ELL3). Associates with CCNT1/cyclin-T1, CCNT2/cyclin-T2 (isoform A and isoform B) or CCNK/cyclin-K to form active P-TEFb. P-TEFb forms a complex with AFF4/AF5Q31 and is part of the super elongation complex (SEC). Component of a complex which is composed of at least 5 members: HTATSF1/Tat-SF1, P-TEFb complex, RNA pol II, SUPT5H and NCL/nucleolin. Associates with UBR5 and forms a transcription regulatory complex composed of CDK9, RNAP II, UBR5 and TFIIS/TCEA1 that can stimulate target gene transcription (e.g. gamma fibrinogen/FGG) by recruiting their promoters. Component of the 7SK snRNP inactive complex which is composed of at least 8 members: P-TEFb (composed of CDK9 and CCNT1/cyclin-T1), HEXIM1, HEXIM2, LARP7, BCDIN3, SART3 proteins and 7SK and U6 snRNAs. This inactive 7SK snRNP complex can also interact with NCOR1 and HDAC3, probably to regulate CDK9 acetylation. Release of P-TEFb from P-TEFb/7SK snRNP complex requires both PP2B to transduce calcium Ca(2+) signaling in response to stimuli (e.g. UV or hexamethylene bisacetamide (HMBA)) and PPP1CA to dephosphorylate Thr-186. This released P-TEFb remains inactive in the pre-initiation complex with BRD4 until new Thr-186 phosphorylation occurs after the synthesis of a short RNA (PubMed:10393184, PubMed:10574912, PubMed:12037670, PubMed:11884399, PubMed:12065898, PubMed:12718890, PubMed:15965233, PubMed:16109376, PubMed:17452463, PubMed:17643375, PubMed:18249148, PubMed:18483222, PubMed:18566585, PubMed:20159561, PubMed:20471948, PubMed:21127351, PubMed:21779453, PubMed:22195968, PubMed:9491887). Interacts with BRD4; to target chromatin binding (PubMed:16109376, PubMed:16109377, PubMed:18483222). Interacts with JMJD6 (PubMed:24360279). Interacts with activated nuclear STAT3 and RELA/p65 (PubMed:17956865, PubMed:18362169). Binds to AR and MYOD1 (PubMed:12037670, PubMed:20980437). Forms a complex composed of CDK9, CCNT1/cyclin-T1, EP300 and GATA4 that stimulates hypertrophy in cardiomyocytes (PubMed:20081228). The large PER complex involved in the repression of transcriptional termination is composed of at least PER2, CDK9, DDX5, DHX9, NCBP1 and POLR2A (By similarity). Interacts with HSF1 (PubMed:27189267). Interacts with TBX21 (By similarity). Isoform 3: binds to KU70/XRCC6 (PubMed:20535204). Interacts with WDR43 (By similarity).SUBUNIT (Microbial infection) Interacts with the acidic/proline-rich region of HIV-1 and HIV-2 Tat via T-loop region and is thus required for HIV to hijack host transcription machinery during its replication through cooperative binding to viral TAR RNA (PubMed:10958691, PubMed:9491887). Interacts with herpes simplex virus 1 protein ICP22; this interaction inhibits the positive transcription elongation factor b (P-TEFb) (PubMed:23029222).TISSUE SPECIFICITY Ubiquitous.INDUCTION By replication stress, in chromatin. Probably degraded by the proteasome upon Thr-186 dephosphorylation.PTM Autophosphorylation at Thr-186, Ser-347, Thr-350, Ser-353, Thr-354 and Ser-357 triggers kinase activity by promoting cyclin and substrate binding (e.g. HIV TAT) upon conformational changes. Thr-186 phosphorylation requires the calcium Ca(2+) signaling pathway, including CaMK1D and calmodulin. This inhibition is relieved by Thr-29 dephosphorylation. However, phosphorylation at Thr-29 is inhibitory within the HIV transcription initiation complex. Phosphorylation at Ser-175 inhibits kinase activity. Can be phosphorylated on either Thr-362 or Thr-363 but not on both simultaneously (PubMed:18566585).PTM Dephosphorylation of Thr-186 by PPM1A and PPM1B blocks CDK9 activity and may lead to CDK9 proteasomal degradation. However, PPP1CA-mediated Thr-186 dephosphorylation is required to release P-TEFb from its inactive P-TEFb/7SK snRNP complex. Dephosphorylation of C-terminus Thr and Ser residues by protein phosphatase-1 (PP1) triggers CDK9 activity, contributing to the activation of HIV-1 transcription.PTM N6-acetylation of Lys-44 promotes kinase activity, whereas acetylation of both Lys-44 and Lys-48 mediated by PCAF/KAT2B and GCN5/KAT2A reduces kinase activity (PubMed:17452463, PubMed:18250157). The acetylated form associates with PML bodies in the nuclear matrix and with the transcriptionally silent HIV-1 genome; deacetylated upon transcription stimulation (PubMed:17452463, PubMed:18250157). Deacetylated by SIRT7, promoting the kinase activity and subsequent 'Ser-2' phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (PubMed:28426094).PTM Polyubiquitinated and thus activated by UBR5. This ubiquitination is promoted by TFIIS/TCEA1 and favors 'Ser-2' phosphorylation of RPB1/POLR2A CTD.DISEASE Chronic activation of CDK9 causes cardiac myocyte enlargement leading to cardiac hypertrophy and confers predisposition to heart failure.MISCELLANEOUS CDK9 inhibition contributes to the anticancer activity of most CDK inhibitors under clinical investigation (PubMed:18423896 and PubMed:21779453). As a retroviruses target during the hijack of host transcription (e.g. HIV), CDK9 inhibitors might become specific antiretroviral agents (PubMed:18423896). May be a target for cardiac hypertrophy future treatments (PubMed:19757441 and PubMed:18423896). May also be a target in anti-inflammatory therapy in innate immunity and systemic inflammation (PubMed:18728388).SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.

UniProtP50750

EQUAL

372

EQUAL

Converted from EntitySet in Reactome

Reactome DB_ID: 6807466

CCNT1,CCNT2,CCNK [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityCCNT1 [nucleoplasm]CCNT2 [nucleoplasm]CCNK [nucleoplasm]

UniProtO60563UniProtO60583UniProtO75909Reactome Database ID Release 75112431Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=112431ReactomeR-HSA-112431

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-112431.2Converted from EntitySet in Reactome

Reactome DB_ID: 6797604

Nascent mRNAs of DNA repair genes regulated by CDK12 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityFANCD2 nascent mRNA [nucleoplasm]BRCA1 nascent mRNA [nucleoplasm]FANCI nascent mRNA [nucleoplasm]ATR nascent mRNA [nucleoplasm]

ENSEMBLENST00000419585ENSEMBLENST00000357654ENSEMBLENST00000310775ENSEMBLENST00000350721

Reactome DB_ID: 112420

DSIF complex [nucleoplasm]

DSIF complex

Reactome DB_ID: 64905

UniProt:P63272 SUPT4H1

SUPT4H1

SUPT4H1SPT4HSUPT4HFUNCTION Component of the DRB sensitivity-inducing factor complex (DSIF complex), which regulates mRNA processing and transcription elongation by RNA polymerase II. DSIF positively regulates mRNA capping by stimulating the mRNA guanylyltransferase activity of RNGTT/CAP1A. DSIF also acts cooperatively with the negative elongation factor complex (NELF complex) to enhance transcriptional pausing at sites proximal to the promoter. Transcriptional pausing may facilitate the assembly of an elongation competent RNA polymerase II complex. DSIF and NELF promote pausing by inhibition of the transcription elongation factor TFIIS/S-II. TFIIS/S-II binds to RNA polymerase II at transcription pause sites and stimulates the weak intrinsic nuclease activity of the enzyme. Cleavage of blocked transcripts by RNA polymerase II promotes the resumption of transcription from the new 3' terminus and may allow repeated attempts at transcription through natural pause sites. DSIF can also positively regulate transcriptional elongation and is required for the efficient activation of transcriptional elongation by the HIV-1 nuclear transcriptional activator, Tat. DSIF acts to suppress transcriptional pausing in transcripts derived from the HIV-1 LTR and blocks premature release of HIV-1 transcripts at terminator sequences.SUBUNIT Interacts with SUPT5H to form DSIF. DSIF interacts with the positive transcription elongation factor b complex (P-TEFb complex), which is composed of CDK9 and cyclin-T (CCNT1 or CCNT2). DSIF interacts with RNA polymerase II, and this interaction is reduced by phosphorylation of the C-terminal domain (CTD) of POLR2A by P-TEFb. DSIF also interacts with the NELF complex, which is composed of NELFA, NELFB, NELFD and NELFE, and this interaction occurs following prior binding of DSIF to RNA polymerase II. DSIF also interacts with PRMT1/HRMT1L2, HTATSF1/TATSF1, RNGTT/CAP1A, PRMT5/SKB1, SUPT6H, and can interact with PIN1.TISSUE SPECIFICITY Widely expressed.SIMILARITY Belongs to the SPT4 family.

UniProtP63272

EQUAL

117

EQUAL

Reactome DB_ID: 3009372

UniProt:O00267 SUPT5H

SUPT5H

SPT5SUPT5HSPT5HFUNCTION Component of the DRB sensitivity-inducing factor complex (DSIF complex), which regulates mRNA processing and transcription elongation by RNA polymerase II. DSIF positively regulates mRNA capping by stimulating the mRNA guanylyltransferase activity of RNGTT/CAP1A. DSIF also acts cooperatively with the negative elongation factor complex (NELF complex) to enhance transcriptional pausing at sites proximal to the promoter. Transcriptional pausing may facilitate the assembly of an elongation competent RNA polymerase II complex. DSIF and NELF promote pausing by inhibition of the transcription elongation factor TFIIS/S-II. TFIIS/S-II binds to RNA polymerase II at transcription pause sites and stimulates the weak intrinsic nuclease activity of the enzyme. Cleavage of blocked transcripts by RNA polymerase II promotes the resumption of transcription from the new 3' terminus and may allow repeated attempts at transcription through natural pause sites. DSIF can also positively regulate transcriptional elongation and is required for the efficient activation of transcriptional elongation by the HIV-1 nuclear transcriptional activator, Tat. DSIF acts to suppress transcriptional pausing in transcripts derived from the HIV-1 LTR and blocks premature release of HIV-1 transcripts at terminator sequences.SUBUNIT Interacts with SUPT4H1 to form DSIF. DSIF interacts with the positive transcription elongation factor b complex (P-TEFb complex), which is composed of CDK9 and cyclin-T (CCNT1 or CCNT2). DSIF interacts with RNA polymerase II, and this interaction is reduced by phosphorylation of the C-terminal domain (CTD) of POLR2A by P-TEFb. DSIF also interacts with the NELF complex, which is composed of NELFA, NELFB, NELFD and NELFE, and this interaction occurs following prior binding of DSIF to RNA polymerase II. DSIF also interacts with PRMT1/HRMT1L2, HTATSF1/TATSF1, RNGTT/CAP1A, PRMT5/SKB1, SUPT6H, and can interact with PIN1. Component of a complex which is at least composed of HTATSF1/Tat-SF1, the P-TEFb complex components CDK9 and CCNT1, RNA polymerase II, SUPT5H, and NCL/nucleolin. Interacts with MCM3AP isoform GANP (PubMed:23652018).TISSUE SPECIFICITY Ubiquitously expressed.PTM Methylated by PRMT1/HRMT1L2 and PRMT5/SKB1. Methylation negatively regulates interaction with P-TEFb and RNA polymerase II.PTM Phosphorylated by CDK7 and CDK9. Phosphorylation by P-TEFb alleviates transcriptional pausing and can stimulate transcriptional elongation from the HIV-1 LTR. P-TEFb dependent phosphorylation is stimulated by the HIV-1 Tat protein. Phosphorylation may also stimulate interaction with PIN1. Bulk phosphorylation occurs predominantly in mitosis.SIMILARITY Belongs to the SPT5 family.

UniProtO00267

phosphorylated residue at unknown position

phosphorylated residue [MOD:00696]

EQUAL

1087

EQUAL

Reactome Database ID Release 75112420Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=112420ReactomeR-HSA-112420

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-112420.1

Reactome DB_ID: 112432

NELF complex [nucleoplasm]

NELF complex

Reactome DB_ID: 112427

UniProt:Q8WX92 NELFB

NELFB

COBRA1NELFBKIAA1182FUNCTION Essential component of the NELF complex, a complex that negatively regulates the elongation of transcription by RNA polymerase II (PubMed:12612062). The NELF complex, which acts via an association with the DSIF complex and causes transcriptional pausing, is counteracted by the P-TEFb kinase complex (PubMed:10199401). May be able to induce chromatin unfolding (PubMed:11739404). Essential for early embryogenesis; plays an important role in maintaining the undifferentiated state of embryonic stem cells (ESCs) by preventing unscheduled expression of developmental genes (By similarity). Plays a key role in establishing the responsiveness of stem cells to developmental cues; facilitates plasticity and cell fate commitment in ESCs by establishing the appropriate expression level of signaling molecules (By similarity). Supports the transcription of genes involved in energy metabolism in cardiomyocytes; facilitates the association of transcription initiation factors with the promoters of the metabolism-related genes (By similarity).FUNCTION (Microbial infection) The NELF complex is involved in HIV-1 latency possibly involving recruitment of PCF11 to paused RNA polymerase II (PubMed:23884411). In vitro, binds weakly to the HIV-1 TAR RNA which is located in the long terminal repeat (LTR) of HIV-1 (PubMed:23884411).SUBUNIT The NELF complex is composed of NELFA, NELFB, NELFCD (isoform NELF-C or isoform NELF-D) and NELFE; the N-terminus of NELFB binds to the NELFA:NELFCD subcomplex (PubMed:12612062). Binds RNA which may help to stabilize the NELF complex on nucleic acid (PubMed:27282391). Interacts with the first BRCT repeat of BRCA1 (PubMed:11739404). Interacts with KIAA1191 (PubMed:21153684). Interacts with NELFE (By similarity).TISSUE SPECIFICITY Widely expressed. Expressed in heart, brain, lung, placenta, liver, skeletal muscle, kidney and pancreas.SIMILARITY Belongs to the NELF-B family.

UniProtQ8WX92

EQUAL

580

EQUAL

Reactome DB_ID: 112426

UniProt:Q9H3P2 NELFA

NELFA

P/OKcl.15WHSC2NELFAFUNCTION Essential component of the NELF complex, a complex that negatively regulates the elongation of transcription by RNA polymerase II. The NELF complex, which acts via an association with the DSIF complex and causes transcriptional pausing, is counteracted by the P-TEFb kinase complex.FUNCTION (Microbial infection) The NELF complex is involved in HIV-1 latency possibly involving recruitment of PCF11 to paused RNA polymerase II.SUBUNIT The NELF complex is composed of NELFA, NELFB, NELFCD (isoform NELF-C or isoform NELF-D) and NELFE; NELFA and NELFCD form a stable subcomplex that binds to the N-terminus of NELFB (PubMed:11387440). In vitro, the NELFA:NELFCD subcomplex binds to ssDNA and ssRNA in a sequence- and structure-dependent manner (PubMed:27282391). Interacts with the RNA polymerase II complex when it is not phosphorylated by P-TEFb (PubMed:10199401).TISSUE SPECIFICITY Ubiquitous. Expressed in heart, brain, placenta, liver, skeletal muscle, kidney and pancreas. Expressed at lower level in adult lung. Expressed in fetal brain, lung, liver and kidney.DOMAIN The HDAg-like domain is essential for transcriptional repression, and mediates the interaction with the RNA polymerase II complex.SIMILARITY Belongs to the NELF-A family.CAUTION PubMed:12612062 has shown that it is not involved in Wolf-Hirschhorn syndrome.

UniProtQ9H3P2

EQUAL

528

EQUAL

Reactome DB_ID: 62907

UniProt:P18615 NELFE

NELFE

RDRDBPNELFEFUNCTION Essential component of the NELF complex, a complex that negatively regulates the elongation of transcription by RNA polymerase II (PubMed:10199401). The NELF complex, which acts via an association with the DSIF complex and causes transcriptional pausing, is counteracted by the P-TEFb kinase complex (PubMed:11940650, PubMed:12612062). Provides the strongest RNA binding activity of the NELF complex and may initially recruit the NELF complex to RNA (PubMed:18303858, PubMed:27282391).FUNCTION (Microbial infection) The NELF complex is involved in HIV-1 latency possibly involving recruitment of PCF11 to paused RNA polymerase II.SUBUNIT The NELF complex is composed of NELFA, NELFB, NELFCD (isoform NELF-C or isoform NELF-D) and NELFE (PubMed:10199401, PubMed:27282391). Interacts with NELFB (By similarity).SUBUNIT (Microbial infection) Binds to the HIV-1 TAR RNA which is located in the long terminal repeat (LTR) of HIV-1.TISSUE SPECIFICITY Widely expressed. Expressed in heart, brain, lung, placenta, liver, skeletal muscle, kidney and pancreas.DOMAIN The RRM domain interacts with RNA, and is essential for NELF complex function. It is however not required for the NELF complex formation.PTM Sumoylated.SIMILARITY Belongs to the RRM NELF-E family.

UniProtP18615

EQUAL

380

EQUAL

Reactome DB_ID: 112428

UniProt:Q8IXH7 NELFCD

NELFCD

NELFDTH1LHSPC130NELFCDTH1FUNCTION Essential component of the NELF complex, a complex that negatively regulates the elongation of transcription by RNA polymerase II (PubMed:12612062). The NELF complex, which acts via an association with the DSIF complex and causes transcriptional pausing, is counteracted by the P-TEFb kinase complex (PubMed:10199401).FUNCTION (Microbial infection) The NELF complex is involved in HIV-1 latency possibly involving recruitment of PCF11 to paused RNA polymerase II.SUBUNIT The NELF complex is composed of NELFA, NELFB, NELFCD (isoform NELF-C or isoform NELF-D) and NELFE; NELFA and NELFCD form a stable subcomplex that binds primarily through NELFCD to the N-terminus of NELFB (PubMed:27282391, PubMed:12612062). Binds RNA which may help to stabilize the NELF complex on nucleic acid (PubMed:27282391). In vitro, the NELFA:NELFCD subcomplex binds to ssDNA and ssRNA in a sequence- and structure-dependent manner (PubMed:27282391). Interacts with ARAF1 (PubMed:11952167). Interacts with PCF11 (PubMed:23884411). Interacts with KAT8 (By similarity).TISSUE SPECIFICITY Widely expressed. Expressed in heart, brain, lung, placenta, liver, skeletal and cardiac muscle, adrenal, thyroid, kidney and pancreas.SIMILARITY Belongs to the NELF-D family.

UniProtQ8IXH7

EQUAL

590

EQUAL

Reactome Database ID Release 75112432Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=112432ReactomeR-HSA-112432

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-112432.1

Reactome DB_ID: 113416

UniProt:Q9Y5B0 CTDP1

CTDP1

CTDP1FCP1FUNCTION Processively dephosphorylates 'Ser-2' and 'Ser-5' of the heptad repeats YSPTSPS in the C-terminal domain of the largest RNA polymerase II subunit. This promotes the activity of RNA polymerase II. Plays a role in the exit from mitosis by dephosphorylating crucial mitotic substrates (USP44, CDC20 and WEE1) that are required for M-phase-promoting factor (MPF)/CDK1 inactivation.SUBUNIT Homodimer. Interacts with GTF2F1. Interacts with WDR77, SNRPB and SNRNP70.TISSUE SPECIFICITY Ubiquitously expressed.PTM Phosphorylated. In the presence of TFIIF, the phosphorylated form has an increased CTD phosphatase activity. The phosphorylation is required for the physical interaction with GTF2F1.

UniProtQ9Y5B0

EQUAL

961

EQUAL

Reactome DB_ID: 113425

RNA Polymerase II holoenzyme complex (hyperphosphorylated):TFIIF complex [nucleoplasm]

RNA Polymerase II holoenzyme complex (hyperphosphorylated):TFIIF complex

Reactome DB_ID: 109909

RNA Polymerase II holoenzyme complex (hyperphosphorylated) [nucleoplasm]

RNA Polymerase II holoenzyme complex (hyperphosphorylated)

p-POLR2Phosphorylated RNA Polymerase II

Reactome DB_ID: 113420

UniProt:P24928 POLR2A

POLR2A

POLR2POLR2AFUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Largest and catalytic component of RNA polymerase II which synthesizes mRNA precursors and many functional non-coding RNAs. Forms the polymerase active center together with the second largest subunit. Pol II is the central component of the basal RNA polymerase II transcription machinery. It is composed of mobile elements that move relative to each other. RPB1 is part of the core element with the central large cleft, the clamp element that moves to open and close the cleft and the jaws that are thought to grab the incoming DNA template. At the start of transcription, a single-stranded DNA template strand of the promoter is positioned within the central active site cleft of Pol II. A bridging helix emanates from RPB1 and crosses the cleft near the catalytic site and is thought to promote translocation of Pol II by acting as a ratchet that moves the RNA-DNA hybrid through the active site by switching from straight to bent conformations at each step of nucleotide addition. During transcription elongation, Pol II moves on the template as the transcript elongates. Elongation is influenced by the phosphorylation status of the C-terminal domain (CTD) of Pol II largest subunit (RPB1), which serves as a platform for assembly of factors that regulate transcription initiation, elongation, termination and mRNA processing. Regulation of gene expression levels depends on the balance between methylation and acetylation levels of tha CTD-lysines (By similarity). Initiation or early elongation steps of transcription of growth-factors-induced immediate early genes are regulated by the acetylation status of the CTD (PubMed:24207025). Methylation and dimethylation have a repressive effect on target genes expression (By similarity).FUNCTION (Microbial infection) Acts as an RNA-dependent RNA polymerase when associated with small delta antigen of Hepatitis delta virus, acting both as a replicate and transcriptase for the viral RNA circular genome.SUBUNIT Component of the RNA polymerase II (Pol II) complex consisting of 12 subunits. Component of a complex which is at least composed of HTATSF1/Tat-SF1, the P-TEFb complex components CDK9 and CCNT1, RNA polymerase II, SUPT5H, and NCL/nucleolin. The large PER complex involved in the repression of transcriptional termination is composed of at least PER2, CDK9, DDX5, DHX9, NCBP1 and POLR2A (active). Interacts (via the C-terminal domain (CTD)) with U2AF2; recruits PRPF19 and the Prp19 complex to the pre-mRNA and may couple transcription to pre-mRNA splicing. Interacts (via the C-terminal domain (CTD)) with SMN1/SMN2; recruits SMN1/SMN2 to RNA Pol II elongation complexes. Interacts via the phosphorylated C-terminal domain with WDR82 and with SETD1A and SETD1B only in the presence of WDR82. When phosphorylated at 'Ser-5', interacts with MEN1; the unphosphorylated form, or phosphorylated at 'Ser-2' does not interact. When phosphorylated at 'Ser-2', interacts with SUPT6H (via SH2 domain). Interacts with RECQL5 and TCEA1; binding of RECQL5 prevents TCEA1 binding. The phosphorylated C-terminal domain interacts with FNBP3 and SYNCRIP. Interacts with ATF7IP. Interacts with DDX5. Interacts with WWP2. Interacts with SETX. Interacts (phosphorylated) with PIH1D1. Interacts (via the C-terminal domain (CTD)) with TDRD3. Interacts with PRMT5. Interacts with XRN2. Interacts with SAFB/SAFB1. Interacts with CCNL1. Interacts with CCNL2, MYO1C, PAF1 and SFRS19. Interacts (via C-terminus) with CMTR1, CTDSP1 and SCAF8. Interacts (via the C-terminal domain (CTD)) with CCNT2 (PubMed:15563843). Interacts with FUS. Interacts with MCM3AP isoform GANP (PubMed:23652018). Interacts with kinase SRPK2; the interaction occurs during the co-transcriptional formation of inappropriate R-loops (PubMed:28076779).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein ICP22; this interaction causes loss of CTD 'Ser-2' phosphorylation from pol II engaged in transcription (PubMed:23029222).DOMAIN The C-terminal domain (CTD) serves as a platform for assembly of factors that regulate transcription initiation, elongation, termination and mRNA processing.PTM The tandem heptapeptide repeats in the C-terminal domain (CTD) can be highly phosphorylated (PubMed:28076779). The phosphorylation activates Pol II. Phosphorylation occurs mainly at residues 'Ser-2' and 'Ser-5' of the heptapeptide repeat and is mediated, at least, by CDK7 and CDK9. CDK7 phosphorylation of POLR2A associated with DNA promotes transcription initiation by triggering dissociation from DNA. Phosphorylation also takes place at 'Ser-7' of the heptapeptide repeat, which is required for efficient transcription of snRNA genes and processing of the transcripts. The phosphorylation state is believed to result from the balanced action of site-specific CTD kinases and phosphatases, and a 'CTD code' that specifies the position of Pol II within the transcription cycle has been proposed. Dephosphorylated by the protein phosphatase CTDSP1.PTM Among tandem heptapeptide repeats of the C-terminal domain (CTD) some do not match the Y-S-P-T-S-P-S consensus, the seventh serine residue 'Ser-7' being replaced by a lysine. 'Lys-7' in these non-consensus heptapeptide repeats can be alternatively acetylated, methylated and dimethylated. EP300 is one of the enzyme able to acetylate 'Lys-7'. Acetylation at 'Lys-7' of non-consensus heptapeptide repeats is associated with 'Ser-2' phosphorylation and active transcription. Regulates initiation or early elongation steps of transcription specially for inducible genes.PTM Methylated at Arg-1810 prior to transcription initiation when the CTD is hypophosphorylated, phosphorylation at Ser-1805 and Ser-1808 preventing this methylation. Symmetrically or asymmetrically dimethylated at Arg-1810 by PRMT5 and CARM1 respectively. Symmetric or asymmetric dimethylation modulates interactions with CTD-binding proteins like SMN1/SMN2 and TDRD3. SMN1/SMN2 interacts preferentially with the symmetrically dimethylated form while TDRD3 interacts with the asymmetric form. Through the recruitment of SMN1/SMN2, symmetric dimethylation is required for resolving RNA-DNA hybrids created by RNA polymerase II, that form R-loop in transcription terminal regions, an important step in proper transcription termination. CTD dimethylation may also facilitate the expression of select RNAs. Among tandem heptapeptide repeats of the C-terminal domain (CTD) some do not match the Y-S-P-T-S-P-S consensus, the seventh serine residue 'Ser-7' being replaced by a lysine. 'Lys-7' in these non-consensus heptapeptide repeats can be alternatively acetylated, methylated, dimethylated and trimethylated. Methylation occurs in the earliest transcription stages and precedes or is concomitant to 'Ser-5' and 'Ser-7' phosphorylation. Dimethylation and trimehtylation at 'Lys-7' of non-consensus heptapeptide repeats are exclusively associated with phosphorylated CTD.PTM Ubiquitinated by WWP2 leading to proteasomal degradation (By similarity). Following UV treatment, the elongating form of RNA polymerase II (RNA pol IIo) is ubiquitinated on UV damage sites without leading to degradation: ubiquitination is facilitated by KIAA1530/UVSSA and promotes RNA pol IIo backtracking to allow access to the nucleotide excision repair machinery.MISCELLANEOUS The binding of ribonucleoside triphosphate to the RNA polymerase II transcribing complex probably involves a two-step mechanism. The initial binding seems to occur at the entry (E) site and involves a magnesium ion temporarily coordinated by three conserved aspartate residues of the two largest RNA Pol II subunits. The ribonucleoside triphosphate is transferred by a rotation to the nucleotide addition (A) site for pairing with the template DNA. The catalytic A site involves three conserved aspartate residues of the RNA Pol II largest subunit which permanently coordinate a second magnesium ion.SIMILARITY Belongs to the RNA polymerase beta' chain family.

UniProtP24928

O-phospho-L-serine at 5

EQUAL

O-phospho-L-serine [MOD:00046]

O-phospho-L-serine at 2

EQUAL

1970

EQUAL

Reactome DB_ID: 83714

UniProt:P61218 POLR2F

POLR2F

POLR2FPOLRFFUNCTION DNA-dependent RNA polymerases catalyze the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I, II, and III which synthesize ribosomal RNA precursors, mRNA precursors and many functional non-coding RNAs, and small RNAs, such as 5S rRNA and tRNAs, respectively. Pol II is the central component of the basal RNA polymerase II transcription machinery. Pols are composed of mobile elements that move relative to each other. In Pol II, POLR2F/RPB6 is part of the clamp element and together with parts of RPB1 and RPB2 forms a pocket to which the RPB4-RPB7 subcomplex binds (By similarity).SUBUNIT Component of the RNA polymerase I (Pol I), RNA polymerase II (Pol II) and RNA polymerase III (Pol III) complexes consisting of at least 13, 12 and 17 subunits, respectively.SIMILARITY Belongs to the archaeal RpoK/eukaryotic RPB6 RNA polymerase subunit family.

UniProtP61218

EQUAL

127

EQUAL

Reactome DB_ID: 63506

UniProt:P19387 POLR2C

POLR2C

A-152E5.7POLR2CFUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of RNA polymerase II which synthesizes mRNA precursors and many functional non-coding RNAs. Pol II is the central component of the basal RNA polymerase II transcription machinery. It is composed of mobile elements that move relative to each other. RPB3 is part of the core element with the central large cleft and the clamp element that moves to open and close the cleft (By similarity).SUBUNIT Component of the RNA polymerase II (Pol II) complex consisting of 12 subunits. RPB11/POLR2J and RPB3/POLR2C subunits interact with each other.SIMILARITY Belongs to the archaeal RpoD/eukaryotic RPB3 RNA polymerase subunit family.

UniProtP19387

EQUAL

275

EQUAL

Reactome DB_ID: 63523

UniProt:P52434 POLR2H

POLR2H

POLR2HFUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I, II and III which synthesize ribosomal RNA precursors, mRNA precursors and many functional non-coding RNAs, and small RNAs, such as 5S rRNA and tRNAs, respectively.SUBUNIT Component of the RNA polymerase I (Pol I), RNA polymerase II (Pol II) and RNA polymerase III (Pol III) complexes consisting of at least 13, 12 and 17 subunits, respectively. Directly interacts with POLR2A.SIMILARITY Belongs to the eukaryotic RPB8 RNA polymerase subunit family.

UniProtP52434

EQUAL

150

EQUAL

Reactome DB_ID: 63531

UniProt:P52435 POLR2J

POLR2J

POLR2J1POLR2JFUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of RNA polymerase II which synthesizes mRNA precursors and many functional non-coding RNAs. Pol II is the central component of the basal RNA polymerase II transcription machinery. It is composed of mobile elements that move relative to each other. RPB11 is part of the core element with the central large cleft (By similarity).SUBUNIT Component of the RNA polymerase II (Pol II) complex consisting of 12 subunits. Interacts with AATF.TISSUE SPECIFICITY Ubiquitously expressed. High expression was found in heart and skeletal muscle.SIMILARITY Belongs to the archaeal RpoL/eukaryotic RPB11/RPC19 RNA polymerase subunit family.

UniProtP52435

EQUAL

117

EQUAL

Reactome DB_ID: 63504

UniProt:P30876 POLR2B

POLR2B

POLR2BFUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Second largest component of RNA polymerase II which synthesizes mRNA precursors and many functional non-coding RNAs. Proposed to contribute to the polymerase catalytic activity and forms the polymerase active center together with the largest subunit. Pol II is the central component of the basal RNA polymerase II transcription machinery. It is composed of mobile elements that move relative to each other. RPB2 is part of the core element with the central large cleft, the clamp element that moves to open and close the cleft and the jaws that are thought to grab the incoming DNA template (By similarity).SUBUNIT Component of the RNA polymerase II (Pol II) complex consisting of 12 subunits. Interacts with WDR82. Interacts with MEN1.MISCELLANEOUS The binding of ribonucleoside triphosphate to the RNA polymerase II transcribing complex probably involves a two-step mechanism. The initial binding seems to occur at the entry (E) site and involves a magnesium ion coordinated by three conserved aspartate residues of the two largest RNA Pol II subunits (By similarity).SIMILARITY Belongs to the RNA polymerase beta chain family.

UniProtP30876

EQUAL

1174

EQUAL

Reactome DB_ID: 63517

UniProt:P62487 POLR2G

POLR2G

RPB7POLR2GFUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of RNA polymerase II which synthesizes mRNA precursors and many functional non-coding RNAs. Pol II is the central component of the basal RNA polymerase II transcription machinery. It is composed of mobile elements that move relative to each other. RPB7 is part of a subcomplex with RPB4 that binds to a pocket formed by RPB1, RPB2 and RPB6 at the base of the clamp element. The RBP4-RPB7 subcomplex seems to lock the clamp via RPB7 in the closed conformation thus preventing double-stranded DNA to enter the active site cleft. The RPB4-RPB7 subcomplex binds single-stranded DNA and RNA (By similarity). Binds RNA.SUBUNIT Component of the RNA polymerase II (Pol II) complex consisting of 12 subunits. RPB4 and RPB7 form a subcomplex that protrudes from the 10-subunit Pol II core complex.SIMILARITY Belongs to the eukaryotic RPB7/RPC8 RNA polymerase subunit family.

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Reactome DB_ID: 83713

UniProt:P19388 POLR2E

POLR2E

POLR2EFUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I, II and III which synthesize ribosomal RNA precursors, mRNA precursors and many functional non-coding RNAs, and small RNAs, such as 5S rRNA and tRNAs, respectively. Pol II is the central component of the basal RNA polymerase II transcription machinery. Pols are composed of mobile elements that move relative to each other. In Pol II, POLR2E/RPB5 is part of the lower jaw surrounding the central large cleft and thought to grab the incoming DNA template. Seems to be the major component in this process (By similarity).SUBUNIT Component of the RNA polymerase I (Pol I), RNA polymerase II (Pol II) and RNA polymerase III (Pol III) complexes consisting of at least 13, 12 and 17 subunits, respectively (By similarity). In RNA Pol II, this subunit is present in 2-fold molar excess over the other subunits. Interacts with URI1.SUBUNIT (Microbial infection) Interacts with HBV protein X.SIMILARITY Belongs to the archaeal RpoH/eukaryotic RPB5 RNA polymerase subunit family.

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Reactome DB_ID: 63537

UniProt:P53803 POLR2K

POLR2K

POLR2KFUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I, II and III which synthesize ribosomal RNA precursors, mRNA precursors and many functional non-coding RNAs, and a small RNAs, such as 5S rRNA and tRNAs, respectively.SUBUNIT Component of the RNA polymerase I (Pol I), RNA polymerase II (Pol II) and RNA polymerase III (Pol III) complexes consisting of at least 13, 12 and 17 subunits, respectively.SIMILARITY Belongs to the archaeal RpoP/eukaryotic RPC10 RNA polymerase subunit family.

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Reactome DB_ID: 63525

UniProt:P36954 POLR2I

POLR2I

POLR2IFUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of RNA polymerase II which synthesizes mRNA precursors and many functional non-coding RNAs. Pol II is the central component of the basal RNA polymerase II transcription machinery. It is composed of mobile elements that move relative to each other. RPB9 is part of the upper jaw surrounding the central large cleft and thought to grab the incoming DNA template (By similarity).SUBUNIT Component of the RNA polymerase II (Pol II) complex consisting of 12 subunits.SIMILARITY Belongs to the archaeal RpoM/eukaryotic RPA12/RPB9/RPC11 RNA polymerase family.

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Reactome DB_ID: 63508

UniProt:O15514 POLR2D

POLR2D

POLR2DFUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Component of RNA polymerase II which synthesizes mRNA precursors and many functional non-coding RNAs. Pol II is the central component of the basal RNA polymerase II transcription machinery. It is composed of mobile elements that move relative to each other. RPB4 is part of a subcomplex with RPB7 that binds to a pocket formed by RPB1, RPB2 and RPB6 at the base of the clamp element. The RBP4-RPB7 subcomplex seems to lock the clamp via RPB7 in the closed conformation thus preventing double-stranded DNA to enter the active site cleft. The RPB4-RPB7 subcomplex binds single-stranded DNA and RNA (By similarity).SUBUNIT Component of the RNA polymerase II (Pol II) complex consisting of 12 subunits. RPB4 and RPB7 form a subcomplex that protrudes from the 10-subunit Pol II core complex.SIMILARITY Belongs to the eukaryotic RPB4 RNA polymerase subunit family.

UniProtO15514

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Reactome DB_ID: 83715

UniProt:P62875 POLR2L

POLR2L

POLR2LFUNCTION DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Common component of RNA polymerases I, II and III which synthesize ribosomal RNA precursors, mRNA precursors and many functional non-coding RNAs, and a small RNAs, such as 5S rRNA and tRNAs, respectively. Pol II is the central component of the basal RNA polymerase II transcription machinery. Pols are composed of mobile elements that move relative to each other. In Pol II, POLR2L/RBP10 is part of the core element with the central large cleft (By similarity).SUBUNIT Component of the RNA polymerase I (Pol I), RNA polymerase II (Pol II) and RNA polymerase III (Pol III) complexes consisting of at least 13, 12 and 17 subunits, respectively.SIMILARITY Belongs to the archaeal RpoN/eukaryotic RPB10 RNA polymerase subunit family.

UniProtP62875

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Reactome Database ID Release 75109909Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=109909ReactomeR-HSA-109909

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-109909.2

Reactome DB_ID: 109631

TFIIF [nucleoplasm]

TFIIF

Reactome DB_ID: 65567

UniProt:P13984 GTF2F2

GTF2F2

RAP30GTF2F2FUNCTION TFIIF is a general transcription initiation factor that binds to RNA polymerase II and helps to recruit it to the initiation complex in collaboration with TFIIB. It promotes transcription elongation. This subunit shows ATP-dependent DNA-helicase activity.SUBUNIT Heterodimer of an alpha and a beta subunit. Interacts with HTATSF1 and GPBP1 (By similarity). Interacts with URI1. Interacts with GTF2B (via N-terminus); this interaction is inhibited in presence of GTF2F1 (PubMed:8504927, PubMed:8662660).SIMILARITY Belongs to the TFIIF beta subunit family.

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Reactome DB_ID: 65565

UniProt:P35269 GTF2F1

GTF2F1

GTF2F1RAP74FUNCTION TFIIF is a general transcription initiation factor that binds to RNA polymerase II and helps to recruit it to the initiation complex in collaboration with TFIIB. It promotes transcription elongation.SUBUNIT Heterodimer of an alpha and a beta subunit. Interacts with GTF2F2, CTDP1, TAF6/TAFII80 and URI1. Interacts with GTF2B (via C-terminus and preferentially via acetylated form); this interaction prevents binding of GTF2B to GTF2F2 (PubMed:8662660, PubMed:12931194).INDUCTION Up-regulated in response to enterovirus 71 (EV71) infection.PTM Phosphorylated on Ser and other residues by TAF1 and casein kinase II-like kinases.SIMILARITY Belongs to the TFIIF alpha subunit family.CAUTION Was reported to have a protein kinase activity and to autophosphorylates on Ser-385 and Thr-389.

UniProtP35269

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Reactome Database ID Release 75109631Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=109631ReactomeR-HSA-109631

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-109631.1Reactome Database ID Release 75113425Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113425ReactomeR-HSA-113425

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-113425.1Reactome Database ID Release 756797609Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6797609ReactomeR-HSA-6797609

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6797609.1

Reactome DB_ID: 112425

Elongin Complex [nucleoplasm]

Elongin Complex

Reactome DB_ID: 112424

Elongin B:C complex [nucleoplasm]

Elongin B:C complex

Reactome DB_ID: 112422

UniProt:Q15369 ELOC

ELOC

TCEB1ELOCFUNCTION SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A is transcriptionally active and its transcription activity is strongly enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex) (PubMed:7821821). In embryonic stem cells, the elongin BC complex is recruited by EPOP to Polycomb group (PcG) target genes in order generate genomic region that display both active and repressive chromatin properties, an important feature of pluripotent stem cells (By similarity).FUNCTION The elongin BC complex seems to be involved as an adapter protein in the proteasomal degradation of target proteins via different E3 ubiquitin ligase complexes, including the von Hippel-Lindau ubiquitination complex CBC(VHL). By binding to BC-box motifs it seems to link target recruitment subunits, like VHL and members of the SOCS box family, to Cullin/RBX1 modules that activate E2 ubiquitination enzymes.SUBUNIT Heterotrimer of an A (ELOA, ELOA2 or ELOA3P), ELOB and ELOC subunit (PubMed:17997974). The elongin BC complex interacts with EPOP; leading to recruit the elongin BC complex to Polycomb group (PcG) target genes, thereby restricting excessive activity of the PRC2/EED-EZH2 complex (By similarity). Part of E3 ubiquitin ligase complexes with CUL5 or CUL2, RBX1 and a substrate adapter protein that can be either SOCS1, SOCS5, ELOA, VHL or WSB1 (PubMed:15590694). The elongin BC complex is part of a complex with VHL and hydroxylated HIF1A (PubMed:12050673, PubMed:12004076). Part of an E3 ubiquitin-protein ligase complex including ZYG11B, CUL2 and Elongin BC. Part of an E3 ubiquitin-protein ligase complex including ZER1, CUL2 and Elongin BC (PubMed:17304241). Interacts with VHL (PubMed:10205047, PubMed:12050673, PubMed:11006129). Interacts with TMF1 (PubMed:15467733). Interacts with SPSB1 (PubMed:17189197). Interacts with SPSB1. Interacts with KLHDC10; which may be an E3 ubiquitin ligase complex substrate recognition component (PubMed:23102700). Interacts with NOS2 in the presence of SPSB1 or SPSB2 or SPSB4 (PubMed:21199876).SUBUNIT (Microbial infection) Substrate adapter protein can be a viral protein such as HIV Vif.SUBUNIT (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein NS1.SUBUNIT (Microbial infection) Interacts with molluscum contagiosum virus MC132.SUBUNIT (Microbial infection) Interacts with herpes virus 8 virus protein LANA1.TISSUE SPECIFICITY Overexpressed in prostate cancer cell line PC-3 and breast cancer cell line SK-BR-3.SIMILARITY Belongs to the SKP1 family.

UniProtQ15369

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Reactome DB_ID: 112423

UniProt:Q15370 ELOB

ELOB

TCEB2ELOBFUNCTION SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A is transcriptionally active and its transcription activity is strongly enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex) (PubMed:7638163). In embryonic stem cells, the elongin BC complex is recruited by EPOP to Polycomb group (PcG) target genes in order generate genomic region that display both active and repressive chromatin properties, an important feature of pluripotent stem cells (By similarity).FUNCTION The elongin BC complex seems to be involved as an adapter protein in the proteasomal degradation of target proteins via different E3 ubiquitin ligase complexes, including the von Hippel-Lindau ubiquitination complex CBC(VHL). By binding to BC-box motifs it seems to link target recruitment subunits, like VHL and members of the SOCS box family, to Cullin/RBX1 modules that activate E2 ubiquitination enzymes.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Heterotrimer of an A (ELOA, ELOA2 or ELOA3), ELOB and ELOC subunit (PubMed:10205047, PubMed:17997974). The elongin BC complex interacts with EPOP; leading to recruit the elongin BC complex to Polycomb group (PcG) target genes, thereby restricting excessive activity of the PRC2/EED-EZH2 complex (By similarity). Part of E3 ubiquitin ligase complexes with CUL5 or CUL2, RBX1 and a substrate adapter protein that can be either SOCS1, SOCS5, ELOA, VHL or WSB1 (PubMed:15590694, PubMed:22286099). Interacts with VHL (PubMed:10205047, PubMed:11006129). Found in a complex composed of LIMD1, VHL, EGLN1/PHD2, ELOB and CUL2. Interacts with SPSB1 (PubMed:17189197). Interacts with KLHDC10; which may be an E3 ubiquitin ligase complex substrate recognition component (PubMed:23102700).SUBUNIT (Microbial infection) Substrate adapter protein can be a viral protein such as HIV Vif.SUBUNIT (Microbial infection) Interacts with molluscum contagiosum virus MC132.SUBUNIT (Microbial infection) Interacts with herpes virus 8 virus protein LANA1.

UniProtQ15370

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Reactome Database ID Release 75112424Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=112424ReactomeR-HSA-112424

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-112424.1Converted from EntitySet in Reactome

Reactome DB_ID: 8867795

Elongin A [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityTCEB3C [nucleoplasm]TCEB3 [nucleoplasm]TCEB3B [nucleoplasm]

UniProtQ8NG57UniProtQ14241UniProtQ8IYF1Reactome Database ID Release 75112425Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=112425ReactomeR-HSA-112425

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-112425.2

Reactome DB_ID: 54257

UniProt:P55199 ELL

ELL

ELLC19orf17FUNCTION Elongation factor component of the super elongation complex (SEC), a complex required to increase the catalytic rate of RNA polymerase II transcription by suppressing transient pausing by the polymerase at multiple sites along the DNA. Elongation factor component of the little elongation complex (LEC), a complex required to regulate small nuclear RNA (snRNA) gene transcription by RNA polymerase II and III (PubMed:22195968, PubMed:23932780). Specifically required for stimulating the elongation step of RNA polymerase II- and III-dependent snRNA gene transcription (PubMed:23932780). ELL also plays an early role before its assembly into in the SEC complex by stabilizing RNA polymerase II recruitment/initiation and entry into the pause site. Required to stabilize the pre-initiation complex and early elongation.SUBUNIT Component of the super elongation complex (SEC), at least composed of EAF1, EAF2, CDK9, MLLT3/AF9, AFF (AFF1 or AFF4), the P-TEFb complex and ELL (ELL, ELL2 or ELL3). Component of the little elongation complex (LEC), at least composed of ELL (ELL, ELL2 or ELL3), ZC3H8, ICE1 and ICE2. Interacts with AFF4; the interaction is direct. Interacts with EAF1 and EAF2. Interacts with ICE1 (via N-terminus domain). Interacts with ICE2. Interacts with USPL1 (PubMed:24413172).TISSUE SPECIFICITY Expressed in all tissues tested. Highest levels found in placenta, skeletal muscle, testis and peripheral blood leukocytes.DISEASE A chromosomal aberration involving ELL is found in acute leukemias. Translocation t(11;19)(q23;p13.1) with KMT2A/MLL1. The result is a rogue activator protein.SIMILARITY Belongs to the ELL/occludin family.

UniProtP55199

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Reactome DB_ID: 65748

UniProt:P23193 TCEA1

TCEA1

TFIISGTF2STCEA1FUNCTION Necessary for efficient RNA polymerase II transcription elongation past template-encoded arresting sites. The arresting sites in DNA have the property of trapping a certain fraction of elongating RNA polymerases that pass through, resulting in locked ternary complexes. Cleavage of the nascent transcript by S-II allows the resumption of elongation from the new 3'-terminus.SUBUNIT Interacts with EAF2 (By similarity). Associates with UBR5 and forms a transcription regulatory complex made of CDK9, RNAP II, UBR5 and TFIIS/TCEA1 that can stimulate target gene transcription (e.g. gamma fibrinogen/FGG) by recruiting their promoters.DISEASE A chromosomal aberration involving TCEA1 may be a cause of salivary gland pleiomorphic adenomas (PA) [181030]. Pleiomorphic adenomas are the most common benign epithelial tumors of the salivary gland. Translocation t(3;8)(p21;q12) with PLAG1.MISCELLANEOUS S-II binds to RNA-polymerase II in the absence of transcription.SIMILARITY Belongs to the TFS-II family.

UniProtP23193

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301

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Reactome DB_ID: 112417

FACT complex [nucleoplasm]

FACT complex

Reactome DB_ID: 112415

UniProt:Q9Y5B9 SUPT16H

SUPT16H

SUPT16HFACT140FACTP140FUNCTION Component of the FACT complex, a general chromatin factor that acts to reorganize nucleosomes. The FACT complex is involved in multiple processes that require DNA as a template such as mRNA elongation, DNA replication and DNA repair. During transcription elongation the FACT complex acts as a histone chaperone that both destabilizes and restores nucleosomal structure. It facilitates the passage of RNA polymerase II and transcription by promoting the dissociation of one histone H2A-H2B dimer from the nucleosome, then subsequently promotes the reestablishment of the nucleosome following the passage of RNA polymerase II. The FACT complex is probably also involved in phosphorylation of 'Ser-392' of p53/TP53 via its association with CK2 (casein kinase II).SUBUNIT Interacts with MYOG (via C-terminal region) (By similarity). Component of the FACT complex, a stable heterodimer of SSRP1 and SUPT16H (PubMed:10421373). Also component of a CK2-SPT16-SSRP1 complex which forms following UV irradiation, composed of SSRP1, SUPT16H, CSNK2A1, CSNK2A2 and CSNK2B (PubMed:11239457, PubMed:12393879). Interacts with NEK9 (PubMed:14660563). Binds to histone H2A-H2B (PubMed:10421373). Identified in a centromere complex containing histones H2A, H2B and H4, and at least CENPA, CENPB, CENPC, CENPT, CENPN, HJURP, SUPT16H, SSRP1 and RSF1 (PubMed:27499292). Interacts with GTF2E2 (PubMed:10792464).SUBUNIT (Microbial infection) Interacts with Herpes simplex virus 1 (HHV-1) protein ICP22; this interaction relocalizes the FACT complex to viral genomes in infected cells.TISSUE SPECIFICITY Ubiquitous.DOMAIN The C-terminal Glu-rich acidic region is essential for FACT activity.PTM ADP-ribosylated. ADP-ribosylation by PARP1 is induced by genotoxic stress and correlates with dissociation of FACT from chromatin.SIMILARITY Belongs to the peptidase M24 family. SPT16 subfamily.CAUTION Although related to the peptidase M24 family, this protein lacks conserved active site residues suggesting that it may lack peptidase activity.

UniProtQ9Y5B9

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1047

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Reactome DB_ID: 65105

UniProt:Q08945 SSRP1

SSRP1

FACT80SSRP1FUNCTION Component of the FACT complex, a general chromatin factor that acts to reorganize nucleosomes. The FACT complex is involved in multiple processes that require DNA as a template such as mRNA elongation, DNA replication and DNA repair. During transcription elongation the FACT complex acts as a histone chaperone that both destabilizes and restores nucleosomal structure. It facilitates the passage of RNA polymerase II and transcription by promoting the dissociation of one histone H2A-H2B dimer from the nucleosome, then subsequently promotes the reestablishment of the nucleosome following the passage of RNA polymerase II. The FACT complex is probably also involved in phosphorylation of 'Ser-392' of p53/TP53 via its association with CK2 (casein kinase II). Binds specifically to double-stranded DNA and at low levels to DNA modified by the antitumor agent cisplatin. May potentiate cisplatin-induced cell death by blocking replication and repair of modified DNA. Also acts as a transcriptional coactivator for p63/TP63.SUBUNIT Interacts with MYOG (via C-terminal region) (By similarity). Component of the FACT complex, a stable heterodimer of SSRP1 and SUPT16H (PubMed:10421373). Also component of a CK2-SPT16-SSRP1 complex which forms following UV irradiation, composed of SSRP1, SUPT16H, CSNK2A1, CSNK2A2 and CSNK2B (PubMed:11239457, PubMed:12393879). Binds to histone H3-H4 tetramers, but not to intact nucleosomes. Identified in a centromere complex containing histones H2A, H2B and H4, and at least CENPA, CENPB, CENPC, CENPT, CENPN, HJURP, SUPT16H, SSRP1 and RSF1 (PubMed:27499292). Interacts with isoform gamma of TP63 (PubMed:12374749). Interacts with FYTTD1/UIF (PubMed:19836239). Interacts with SRF (By similarity). Interacts with NEK9 (PubMed:14660563).SUBUNIT (Microbial infection) Interacts with Herpes simplex virus 1 (HHV-1) protein ICP22; this interaction relocalizes the FACT complex to viral genomes in infected cells.DOMAIN The HMG box DNA-binding domain mediates DNA-binding. It has both affinity and specificity for DNA damaged globally with cisplatin.PTM Phosphorylated by CK2 following UV but not gamma irradiation. Phosphorylation inhibits its DNA-binding activity.PTM Ubiquitinated. Polyubiquitinated following caspase cleavage resulting in degradation of the N-terminal ubiquitinated part of the cleaved protein.PTM Sumoylated.MISCELLANEOUS Autoantibodies against SSRP1 are present in sera from patients with systemic lupus erythematosus, but not other rheumatic diseases.SIMILARITY Belongs to the SSRP1 family.

UniProtQ08945

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709

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Reactome Database ID Release 75112417Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=112417ReactomeR-HSA-112417

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-112417.1Reactome Database ID Release 756797611Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6797611ReactomeR-HSA-6797611

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6797611.1

Reactome DB_ID: 6797095

CCNK:CDK12 [nucleoplasm]

CCNK:CDK12

Reactome DB_ID: 6797012

UniProt:Q9NYV4 CDK12

CDK12

CRK7CDK12CRKRSKIAA0904FUNCTION Cyclin-dependent kinase that phosphorylates the C-terminal domain (CTD) of the large subunit of RNA polymerase II (POLR2A), thereby acting as a key regulator of transcription elongation. Regulates the expression of genes involved in DNA repair and is required for the maintenance of genomic stability. Preferentially phosphorylates 'Ser-5' in CTD repeats that are already phosphorylated at 'Ser-7', but can also phosphorylate 'Ser-2'. Required for RNA splicing, possibly by phosphorylating SRSF1/SF2. Involved in regulation of MAP kinase activity, possibly leading to affect the response to estrogen inhibitors.ACTIVITY REGULATION Inhibited by the ATP analog flavopiridol, purvalanol A, purvalanol B, staurosporine and CR8.SUBUNIT Interacts with CCNL1 and CCNL2 (By similarity). Interacts with CCNK.TISSUE SPECIFICITY Ubiquitously expressed.PTM Phosphorylation at Thr-893 increases kinase activity.DISEASE Chromosomal aberrations involving CDK12 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with ERBB2, leading to CDK12-ERBB2 fusion leading to trunctated CDK12 protein not in-frame with ERBB2.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.

UniProtQ9NYV4

EQUAL

1490

EQUAL

Reactome DB_ID: 6796619

UniProt:O75909 CCNK

CCNK

CPR4CCNKFUNCTION Regulatory subunit of cyclin-dependent kinases that mediates activation of target kinases. Plays a role in transcriptional regulation via its role in regulating the phosphorylation of the C-terminal domain (CTD) of the large subunit of RNA polymerase II (POLR2A).SUBUNIT Regulatory subunit of cyclin-dependent kinases. Identified in a complex with a kinase and the RNA polymerase II holoenzyme. Interacts with POLR2A. Interacts with CDK12 and CDK13. Interacts with CDK9 according to PubMed:10574912; does not interact with CDK9 according to PubMed:22012619.TISSUE SPECIFICITY Widely expressed. Highest levels in testis.SIMILARITY Belongs to the cyclin family. Cyclin C subfamily.

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580

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Reactome Database ID Release 756797095Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6797095ReactomeR-HSA-6797095

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6797095.1Reactome Database ID Release 756797614Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6797614ReactomeR-HSA-6797614

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6797614.1

Reactome DB_ID: 29358

ATP(4-) [ChEBI:30616]

ATP(4-)

Adenosine 5'-triphosphateatpATP

ChEBI30616

Reactome DB_ID: 6797602

CCNK:CDK12:CDK12-Phosphorylated Elongation Complex at DNA repair genes [nucleoplasm]

CCNK:CDK12:CDK12-Phosphorylated Elongation Complex at DNA repair genes

Reactome DB_ID: 6797607

CDK12-Phosphorylated Elongation Complex [nucleoplasm]

CDK12-Phosphorylated Elongation Complex

Reactome DB_ID: 109634

Reactome DB_ID: 112425

Reactome DB_ID: 54257

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621

EQUAL

Reactome DB_ID: 65748

EQUAL

301

EQUAL

Reactome DB_ID: 6797608

CDK12-phosphorylated RNA Pol II at DNA repair genes [nucleoplasm]

CDK12-phosphorylated RNA Pol II at DNA repair genes

Converted from EntitySet in Reactome

Reactome DB_ID: 6797615

Reactome DB_ID: 112431

Converted from EntitySet in Reactome

Reactome DB_ID: 6797604

Reactome DB_ID: 112420

Reactome DB_ID: 112432

Reactome DB_ID: 113416

EQUAL

961

EQUAL

Reactome DB_ID: 6797705

p-3S-RNA Pol II:TFIIF [nucleoplasm]

p-3S-RNA Pol II:TFIIF

RNA Polymerase II holoenzyme complex phosphorylated by CDK12:TFIIF complex

Reactome DB_ID: 6797702

RNA Polymerase II holoenzyme complex phosphorylated by CDK12 [nucleoplasm]

RNA Polymerase II holoenzyme complex phosphorylated by CDK12

p-3S-RNA Pol II

Reactome DB_ID: 83714

EQUAL

127

EQUAL

Reactome DB_ID: 63506

EQUAL

275

EQUAL

Reactome DB_ID: 63523

EQUAL

150

EQUAL

Reactome DB_ID: 6797701

O-phospho-L-serine at unknown position

EQUAL

1970

EQUAL

Reactome DB_ID: 63531

EQUAL

117

EQUAL

Reactome DB_ID: 63504

EQUAL

1174

EQUAL

Reactome DB_ID: 63517

EQUAL

172

EQUAL

Reactome DB_ID: 83713

EQUAL

210

EQUAL

Reactome DB_ID: 63537

EQUAL

Reactome DB_ID: 63525

EQUAL

125

EQUAL

Reactome DB_ID: 63508

EQUAL

142

EQUAL

Reactome DB_ID: 83715

EQUAL

Reactome Database ID Release 756797702Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6797702ReactomeR-HSA-6797702

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6797702.1

Reactome DB_ID: 109631

Reactome Database ID Release 756797705Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6797705ReactomeR-HSA-6797705

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6797705.1Reactome Database ID Release 756797608Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6797608ReactomeR-HSA-6797608

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6797608.1

Reactome DB_ID: 112417

Reactome Database ID Release 756797607Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6797607ReactomeR-HSA-6797607

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6797607.1

Reactome DB_ID: 6797095

Reactome Database ID Release 756797602Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6797602ReactomeR-HSA-6797602

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6797602.1

Reactome DB_ID: 113582

ADP(3-) [ChEBI:456216]

ADP(3-)

ADP trianion5'-O-[(phosphonatooxy)phosphinato]adenosineADP

ChEBI456216PHYSIOL-LEFT-TO-RIGHT

ACTIVATION

Reactome DB_ID: 6797614

GO0004693

GO molecular function

Reactome Database ID Release 756797610Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6797610Reactome Database ID Release 756797606Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6797606ReactomeR-HSA-6797606

Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6797606.125561469Pubmed2015Characterization of human cyclin-dependent kinase 12 (CDK12) and CDK13 complexes in C-terminal domain phosphorylation, gene transcription, and RNA processingLiang, KaiweiGao, XinGilmore, Joshua MFlorens, Laurence AWashburn, Michael PSmith, EdwinShilatifard, AMol. Cell. Biol. 35:928-3822988298Pubmed2012Interaction of cyclin-dependent kinase 12/CrkRS with cyclin K1 is required for the phosphorylation of the C-terminal domain of RNA polymerase IICheng, S-W GraceKuzyk, Michael AMoradian, AnnieIchu, Taka-AkiChang, Vicky C-DTien, Jerry FVollett, Sarah EGriffith, MalachiMarra, Marco AMorin, Gregg BMol. Cell. Biol. 32:4691-70425429106Pubmed2015Expression, purification, and identification of associated proteins of the full-length hCDK12/CyclinK complexBartkowiak, BartlomiejGreenleaf, Arno LJ. Biol. Chem. 290:1786-9524662513Pubmed2014The structure and substrate specificity of human Cdk12/Cyclin KBösken, Christian AFarnung, LucasHintermair, CorinnaMerzel Schachter, MiriamVogel-Bachmayr, KarinBlazek, DaliborAnand, KanchanFisher, Robert PEick, DirkGeyer, MatthiasNat Commun 5:350522012619Pubmed2011The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genesBlazek, DaliborKohoutek, JiriBartholomeeusen, KoenJohansen, EricHulinkova, PetraLuo, ZepingCimermancic, PeterUle, JernejPeterlin, B MatijaGenes Dev. 25:2158-72