The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes.
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.
Department of Medicine, Microbiology, and Immunology, Rosalind Russell Medical Research Center, University of California at San Francisco (UCSF), USA. dblazek@med.muni.cz
Dalibor
D
Blazek
Jiri
J
Kohoutek
Koen
K
Bartholomeeusen
Eric
E
Johansen
Petra
P
Hulinkova
Zeping
Z
Luo
Peter
P
Cimermancic
Jernej
J
Ule
B Matija
BM
Peterlin
D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism*; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D042822:Genomic Instability; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation
C113028:CCNK protein, human; D016213:Cyclins; D016203:CDC2 Protein Kinase; C447339:CDK12 protein, human; C072262:CDK13 protein, human; D042863:Cyclin-Dependent Kinase 9; D018844:Cyclin-Dependent Kinases