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@article{970731,
author = {Blažek, Dalibor and Kohoutek, Jiří and Bartholomeeusen, Koen and Johansen, Eric and Hulinková, Petra and Luo, Zeping P. and Cimermancic, Peter and Ule, Jernej and Peterlin, Matija B.},
article_location = {Spojené státy americké},
article_number = {20},
doi = {http://dx.doi.org/10.1101/gad.16962311},
keywords = {P-TEFb; Cdk12; CycK; Cdk9; DNA damage; transcription},
language = {eng},
issn = {0890-9369},
journal = {Genes & Development},
title = {The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes},
url = {http://www.genesdev.org/cgi/doi/10.1101/gad.16962311},
volume = {25},
year = {2011}
}
TY - JOUR
ID - 970731
AU - Blažek, Dalibor - Kohoutek, Jiří - Bartholomeeusen, Koen - Johansen, Eric - Hulinková, Petra - Luo, Zeping P. - Cimermancic, Peter - Ule, Jernej - Peterlin, Matija B.
PY - 2011
TI - The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes
JF - Genes & Development
VL - 25
IS - 20
SP - 2158-2172
EP - 2158-2172
PB - Cold Spring Harbor Laboratory Press
SN - 08909369
KW - P-TEFb
KW - Cdk12
KW - CycK
KW - Cdk9
KW - DNA damage
KW - transcription
UR - http://www.genesdev.org/cgi/doi/10.1101/gad.16962311
L2 - http://www.genesdev.org/cgi/doi/10.1101/gad.16962311
N2 - 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.
ER -
BLAŽEK, Dalibor, Jiří KOHOUTEK, Koen BARTHOLOMEEUSEN, Eric JOHANSEN, Petra HULINKOVÁ, Zeping P. LUO, Peter CIMERMANCIC, Jernej ULE and Matija B. PETERLIN. The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. \textit{Genes \&{} Development}. Spojené státy americké: Cold Spring Harbor Laboratory Press, 2011, vol.~25, No~20, p.~2158-2172. ISSN~0890-9369. Available from: https://dx.doi.org/10.1101/gad.16962311.
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