A role for cdk9-cyclin k in maintaining genome integrity

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.

Acknowledgements

This work was supported by a National Cancer Institute grant (R01CA136933) to D.C., the Vanderbilt Center in Molecular Toxicology (P30ES000267), Vanderbilt Ingram Cancer Center and Vanderbilt Institute for Clinical and Translational Research (UL1024975), a Department of Defense Breast Cancer Research Program Era of Hope Postdoctoral Award to D.S.Y., and a National Cancer Institute grant (K08CA143902) to D.S.Y., who is a Georgia Cancer Coalition Distinguished Cancer Scholar.

Figures and Tables

Figure 1 Proposed model for CDK9-cyclin K in the Replication Stress Response. CDK9 has multiple functions. With cyclin T, CDK9 functions in promoting RNA polymerase II elongation. In response to replication stress, CDK9 with cyclin K is mobilized to chromatin where it functions to prevent the breakdown of stalled replication forks and promote cell cycle recovery. CDK9-cyclin K interacts in a complex with ATR and other DNA damage response and repair proteins but likely functions downstream or in a parallel pathway to ATR and CHK1.