R-RESCOVITINE ( SELICICLIB ) INHIBITS DNA DAMAGE-INDUCED CYCLIN A! UP-REGOLATION AND HINDERS NON-HOMOLOGOUS END JOINING: A RATIONAL FOR THERAPEUTIC COMBINATIONS WITH DNA DAMAGING AGENTS

CDK-inhibitors can diminish transcriptional levels of cell cycle-related cyclins through the inhibition of E2F family members and CDK7 and 9. Cyclin A1, an E2F-independent cyclin, is strongly up-regulated under genotoxic conditions and functionally was shown to increase NHEJ activity. Cyclin A1 outcompetes with cyclin A2 for CDK2 binding, possibly redirecting its activity towards DNA repair. To see if we could therapeutically block this switch, we analyzed the effects of the CDKinhibitor R-Roscovitine on the expression levels of cyclin A1 under genotoxic stress and observed subsequent DNA damage and repair mechanisms.