DOI: 10.1101/gad.16962311. The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes

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

10.1101/gad.16962311

Crossref journal-article

Cold Spring Harbor Laboratory

Genes & Development (246)

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.

Bibliography

Blazek, D., Kohoutek, J., Bartholomeeusen, K., Johansen, E., Hulinkova, P., Luo, Z., Cimermancic, P., Ule, J., & Peterlin, B. M. (2011). The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. Genes & Development, 25(20), 2158â2172.

Authors 9

Dalibor Blazek (first)
Jiri Kohoutek (additional)
Koen Bartholomeeusen (additional)
Eric Johansen (additional)
Petra Hulinkova (additional)
Zeping Luo (additional)
Peter Cimermancic (additional)
Jernej Ule (additional)
B. Matija Peterlin (additional)

References 57 Referenced 430

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Dates

Type	When
Created	13 years, 10 months ago (Oct. 19, 2011, 3:38 p.m.)
Deposited	3 years, 9 months ago (Nov. 16, 2021, 9:55 p.m.)
Indexed	3 days, 22 hours ago (Aug. 19, 2025, 6:45 a.m.)
Issued	13 years, 10 months ago (Oct. 15, 2011)
Published	13 years, 10 months ago (Oct. 15, 2011)
Published Online	13 years, 10 months ago (Oct. 19, 2011)
Published Print	13 years, 10 months ago (Oct. 15, 2011)

Funders 0

None

BibTeX

@article{Blazek_2011, title={The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes}, volume={25}, ISSN={1549-5477}, url={http://dx.doi.org/10.1101/gad.16962311}, DOI={10.1101/gad.16962311}, number={20}, journal={Genes & Development}, publisher={Cold Spring Harbor Laboratory}, author={Blazek, Dalibor and Kohoutek, Jiri and Bartholomeeusen, Koen and Johansen, Eric and Hulinkova, Petra and Luo, Zeping and Cimermancic, Peter and Ule, Jernej and Peterlin, B. Matija}, year={2011}, month=oct, pages={2158–2172} }

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