Search results for POLR2A

Showing 12 results out of 12

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Protein (7 results from a total of 7)

Identifier: R-HSA-63502
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: POLR2A: P24928
Identifier: R-HSA-77100
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: POLR2A: P24928
Identifier: R-HSA-6810226
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: POLR2A: P24928
The C-terminal domain (CTD) of POLR2A contains about 52 repeats of the consensus heptad YSPTSPS. Serines-2,5, and 7 of the heptads are phosphorylated in RNA polymerase II initiating transcription of snRNA genes. The exact repeats that are phosphorylated are not known.
Identifier: R-HSA-113420
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: POLR2A: P24928
The C-terminal domain (CTD) of POLR2A contains about 52 repeats of the consensus heptad YSPTSPS. Serines-2 and 5 of the heptads are phosphorylated in RNA polymerase II initiating transcription of protein coding genes. The exact repeats that are phosphorylated are not known.
Identifier: R-HSA-6797701
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: P24928
Identifier: R-HSA-6814543
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: P24928
The C-terminal domain (CTD) of POLR2A contains about 52 repeats of the consensus heptad YSPTSPS. Serines-2,5, and 7 of the heptads are phosphorylated in RNA polymerase II initiating transcription of snRNA genes. The exact repeats that are phosphorylated are not known.
Identifier: R-HSA-6781855
Species: Homo sapiens
Compartment: nucleoplasm
Primary external reference: UniProt: P24928

Reaction (4 results from a total of 4)

Identifier: R-HSA-6797606
Species: Homo sapiens
Compartment: nucleoplasm
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).
Identifier: R-HSA-6781867
Species: Homo sapiens
Compartment: nucleoplasm
The ubiquitin ligase complex ERCC8:DDB1:CUL4:RBX1 may ubiquitinate ERCC6 (CSB) (Groisman et al. 2006) at the later steps of TC-NER and may also be required in the ubiquitination of the RNA Pol II subunit POLR2A in response to damage (Bregman et al. 1996, Lee et al. 2002). Ubiquitination mediated by ERCC8 (CSA) containing ubiquitin ligase complex plays an important role in progression and termination of transcription-coupled nucleotide excision repair (TC-NER), although the mechanistic details are largely unknown.
Identifier: R-HSA-6797712
Species: Homo sapiens
Compartment: nucleoplasm
CDK12-mediated phosphorylation of the C-terminal domain (CTD) of the RNA polymerase II (RNA Pol II) subunit POLR2A (Rpb1) positively regulates transcription and, hence, expression of a set of DNA repair genes that encode long primary transcripts. CDK12, in complex with the TP53-regulated CCNK (cyclin K), phosphorylates POLR2A that was pre-phosphorylated by the CDK9-containing complex P-TEFb. CDK12-mediated phosphorylation of POLR2A is thought to increase the processivity of the RNA Pol II, enabling efficient transcription of long DNA repair genes (Blazek et al. 2011, Cheng et al. 2012, Bosken et al. 2014, Bartkowiak and Greenleaf 2015). CDK12 was shown to colocalize with the RNA Pol II complex at FANCD2, FANCI, ATM, CHEK1, MDC1, RAD51D and ATR gene loci (Ekumi et al. 2015) and to be necessary for achieving sufficient BRCA1 expression (Blazek et al. 2011). CDK12 positively regulates the expression of APEX1, involved in base excision repair (Liang et al. 2015). Recurrent CDK12 mutations are found in ovarian cancer. These mutations affect either the catalytic cleft of CDK12 or disable the interaction of CDK12 with CCNK, resulting in the loss of CDK12 function. Ovarian tumors that harbour inactivating CDK12 mutations exhibit decreased BRCA1 levels, defective homologous recombination repair, increased sensitivity to DNA crosslinking agents, and sensitivity to PARP inhibitors (Joshi et al. 2014, Ekumi et al. 2015).
Identifier: R-HSA-6810233
Species: Homo sapiens
Compartment: nucleoplasm
CDK7 phosphorylates serine-5 residues of heptad repeats (consensus YSPTSPS) in the C-terminal domain (CTD) of the large subunit (POLR2A) of RNA polymerase II. Serine-7 residues of the heptad repeats are also phosphorylated at promoters of snRNA genes (Egloff et al. 2007) and CDK7 is required for phosphorylation of serine-7 in vivo (Glover-Cutter et al. 2009). P-TEFb and DNA-PK are able to phosphorylate serine-7 in vitro (Glover-Cutter et al. 2009, Egloff et al. 2010). Impairment of CTD phosphorylation does not appear to affect transcription of snRNA genes but rather impairs 3' processing of the pre-snRNA (Medlin et al. 2003, Jacobs et al. 2004).

Pathway (1 results from a total of 1)

Identifier: R-HSA-6796648
Species: Homo sapiens
Several DNA repair genes contain p53 response elements and their transcription is positively regulated by TP53 (p53). TP53-mediated regulation probably ensures increased protein level of DNA repair genes under genotoxic stress.

TP53 directly stimulates transcription of several genes involved in DNA mismatch repair, including MSH2 (Scherer et al. 2000, Warnick et al. 2001), PMS2 and MLH1 (Chen and Sadowski 2005). TP53 also directly stimulates transcription of DDB2, involved in nucleotide excision repair (Tan and Chu 2002), and FANCC, involved in the Fanconi anemia pathway that repairs DNA interstrand crosslinks (Liebetrau et al. 1997). Other p53 targets that can influence DNA repair functions are RRM2B (Kuo et al. 2012), XPC (Fitch et al. 2003), GADD45A (Amundson et al. 2002), CDKN1A (Cazzalini et al. 2010) and PCNA (Xu and Morris 1999). Interestingly, the responsiveness of some of these DNA repair genes to p53 activation has been shown in human cells but not for orthologous mouse genes (Jegga et al. 2008, Tan and Chu 2002). Contrary to the positive modulation of nucleotide excision repair (NER) and mismatch repair (MMR), p53 can negatively modulate base excision repair (BER), by down-regulating the endonuclease APEX1 (APE1), acting in concert with SP1 (Poletto et al. 2016).

Expression of several DNA repair genes is under indirect TP53 control, through TP53-mediated stimulation of cyclin K (CCNK) expression (Mori et al. 2002). CCNK is the activating cyclin for CDK12 and CDK13 (Blazek et al. 2013). The complex of CCNK and CDK12 binds and phosphorylates the C-terminal domain of the RNA polymerase II subunit POLR2A, which is necessary for efficient transcription of long DNA repair genes, including BRCA1, ATR, FANCD2, FANCI, ATM, MDC1, CHEK1 and RAD51D. Genes whose transcription is regulated by the complex of CCNK and CDK12 are mainly involved in the repair of DNA double strand breaks and/or the Fanconi anemia pathway (Blazek et al. 2011, Cheng et al. 2012, Bosken et al. 2014, Bartkowiak and Greenleaf 2015, Ekumi et al. 2015).

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