Cyclin-dependent kinase 9-cyclin K functions in the replication stress response.

Yu DS, Zhao R, Hsu EL, Cayer J, Ye F, Guo Y, Shyr Y, Cortez D
EMBO Rep. 2010 11 (11): 876-82

PMID: 20930849 · PMCID: PMC2966956 · DOI:10.1038/embor.2010.153

Cyclin-dependent kinase 9 (CDK9) is a well-characterized subunit of the positive transcription elongation factor b complex in which it regulates transcription elongation in cooperation with cyclin T. However, CDK9 also forms a complex with cyclin K, the function of which is less clear. Using a synthetic lethal RNA interference screen in human cells, we identified CDK9 as a component of the replication stress response. Loss of CDK9 activity causes an increase in spontaneous levels of DNA damage signalling in replicating cells and a decreased ability to recover from a transient replication arrest. This activity is restricted to CDK9-cyclin K complexes and is independent of CDK9-cyclin T complex. CDK9 accumulates on chromatin in response to replication stress and limits the amount of single-stranded DNA in cells under stress. Furthermore, we show that CDK9 and cyclin K interact with ataxia telangiectasia and Rad3-related protein and other checkpoint signalling proteins. These results reveal an unexpectedly direct role for CDK9-cyclin K in checkpoint pathways that maintain genome integrity in response to replication stress.

MeSH Terms (13)

Cell Cycle Cell Line, Tumor Chromatin Cyclin-Dependent Kinase 9 Cyclins DNA DNA Replication Gene Silencing Humans Hydroxyurea Protein Binding Replication Protein A Stress, Physiological

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