CDK12 stimulates expression of DNA repair genes

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R-HSA-6797712
Type
Reaction [omitted]
Species
Homo sapiens
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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).

Literature References
PubMed ID Title Journal Year
25429106 Expression, purification, and identification of associated proteins of the full-length hCDK12/CyclinK complex

Bartkowiak, B, Greenleaf, AL

J. Biol. Chem. 2015
25712099 Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex

Ekumi, KM, Paculova, H, Lenasi, T, Pospichalova, V, Bösken, CA, Rybarikova, J, Bryja, V, Geyer, M, Blazek, D, Barboric, M

Nucleic Acids Res. 2015
24662513 The structure and substrate specificity of human Cdk12/Cyclin K

Bösken, CA, Farnung, L, Hintermair, C, Merzel Schachter, M, Vogel-Bachmayr, K, Blazek, D, Anand, K, Fisher, RP, Eick, D, Geyer, M

Nat Commun 2014
25561469 Characterization of human cyclin-dependent kinase 12 (CDK12) and CDK13 complexes in C-terminal domain phosphorylation, gene transcription, and RNA processing

Liang, K, Gao, X, Gilmore, JM, Florens, LA, Washburn, MP, Smith, E, Shilatifard, A

Mol. Cell. Biol. 2015
24554720 Ovarian cancer-associated mutations disable catalytic activity of CDK12, a kinase that promotes homologous recombination repair and resistance to cisplatin and poly(ADP-ribose) polymerase inhibitors

Joshi, PM, Sutor, SL, Huntoon, CJ, Karnitz, LM

J. Biol. Chem. 2014
22988298 Interaction of cyclin-dependent kinase 12/CrkRS with cyclin K1 is required for the phosphorylation of the C-terminal domain of RNA polymerase II

Cheng, SW, Kuzyk, MA, Moradian, A, Ichu, TA, Chang, VC, Tien, JF, Vollett, SE, Griffith, M, Marra, MA, Morin, GB

Mol. Cell. Biol. 2012
22012619 The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes

Blazek, D, Kohoutek, J, Bartholomeeusen, K, Johansen, E, Hulinkova, P, Luo, Z, Cimermancic, P, Ule, J, Peterlin, BM

Genes Dev. 2011
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