CDK12 phosphorylates RNA Pol II CTD at DNA repair genes

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R-HSA-6797606
Type
Reaction [transition]
Species
Homo sapiens
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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).

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

Bartkowiak, B, Greenleaf, AL

J. Biol. Chem. 2015
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
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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Catalyst Activity
Title
cyclin-dependent protein serine/threonine kinase activity of CCNK:CDK12:Elongation Complex at DNA Repair Genes [nucleoplasm]
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