Abstract
Cyclin-dependent kinase 9 (CDK9), with its cyclin T regulatory subunit, is a component of the positive transcription elongation factor b (P-TEFb) complex, which stimulates transcription elongation and also functions in co-transcriptional histone modification, mRNA processing, and mRNA export. CDK9 also binds to cyclin K but the function of this CDK9-cyclin K complex is less clear. We and others have recently shown that CDK9 functions directly in maintaining genome integrity. This activity is restricted to CDK9-cyclin K. Depletion of CDK9 or its cyclin K but not cyclin T regulatory subunit impairs cell cycle recovery in response to replication stress and induces spontanous DNA damage in replicating cells. CDK9-cyclin K also interacts with ATR and other DNA damage response and DNA repair proteins. CDK9 accumulates on chromatin and limits the amount of single-stranded DNA in response to replication stress. Collectively, these data are consistent with a model in which CDK9 responds to replication stress by localizing to chromatin to reduce the breakdown of stalled replication forks and promote recovery from replication arrest. The direct role of CDK9-cyclin K in pathways that maintain genome integrity in response to replication stress appear to be evolutionarily conserved.
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