Disruption of dna repair by cell cycle and transcriptional cdk inhibition

The eukaryotic cell cycle is a tightly regulated series of events coordinated by the periodic activation of members of the cyclin dependent kinases (CDK) family. In addition, a subset of CDK family members play critical roles in transcriptional regulation. Dysregulation of CDK activity by a variety of genetic and epigenetic mechanisms is universally observed in cancer and is thought to be a primary driving force in carcinogenesis, such that there has been longstanding interest in targeting CDKs for cancer therapy. Along with orchestrating the cell cycle and transcriptional events, CDKs have also been directly implicated in the DNA damage response. CDK activity governs cell cycle phase and thus indirectly affects double strand break (DSB) repair pathway choice. Recent evidence also directly implicates CDKs 1 and 2 in homologous recombination DNA repair (HRR) since their activities are crucial at early stages of the repair pathway. These findings suggest that CDK inhibition may not only address aberrant cell proliferation, but may also sensitize cells to a variety of DNA damaging agents as well as PARP inhibition.