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

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:
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
EMBO Rep.
Date: Nov. 01, 2010
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