The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes

Dalibor Blazek, Jiri Kohoutek, Koen Bartholomeeusen, Eric Johansen, Petra Hulinkova, Zeping Luo, Peter Cimermancic, Jernej Ule, B Matija Peterlin

Research output: Contribution to journalA2: International peer reviewed article (not A1-type)

Abstract

Various cyclin-dependent kinase (Cdk) complexes have been implicated in the regulation of transcription. In this study, we identified a 70-kDa Cyclin K (CycK) that binds Cdk12 and Cdk13 to form two different complexes (CycK/Cdk12 or CycK/Cdk13) in human cells. The CycK/Cdk12 complex regulates phosphorylation of Ser2 in the C-terminal domain of RNA polymerase II and expression of a small subset of human genes, as revealed in expression microarrays. Depletion of CycK/Cdk12 results in decreased expression of predominantly long genes with high numbers of exons. The most prominent group of down-regulated genes are the DNA damage response genes, including the critical regulators of genomic stability: BRCA1 (breast and ovarian cancer type 1 susceptibility protein 1), ATR (ataxia telangiectasia and Rad3-related), FANCI, and FANCD2. We show that CycK/Cdk12, rather than CycK/Cdk13, is necessary for their expression. Nuclear run-on assays and chromatin immunoprecipitations with RNA polymerase II on the BRCA1 and FANCI genes suggest a transcriptional defect in the absence of CycK/Cdk12. Consistent with these findings, cells without CycK/Cdk12 induce spontaneous DNA damage and are sensitive to a variety of DNA damage agents. We conclude that through regulation of expression of DNA damage response genes, CycK/Cdk12 protects cells from genomic instability. The essential role of CycK for organisms in vivo is further supported by the result that genetic inactivation of CycK in mice causes early embryonic lethality.

Original languageEnglish
JournalGenes & Development
Volume25
Issue number20
Pages (from-to)2158-2172
Number of pages15
ISSN0890-9369
DOIs
Publication statusPublished - 2011
Externally publishedYes

Fingerprint

Dive into the research topics of 'The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes'. Together they form a unique fingerprint.

Cite this