HIPK2 regulates homology-directed DNA repair and PARP inhibitor sensitivity

Abstract

Repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) counteracts genome instability and carcinogenesis. Cancer cells frequently show defects in HR which can be therapeutically exploited by hypersensitivity to poly(ADP-ribose) polymerase inhibitor (PARPi) treatment. Here we identify an unforeseen function of HIPK2 in HR repair and PARPi sensitivity. HIPK2 accumulates at DSBs and associates with DSB repair factors at DNA damage foci. DSB recruitment of HIPK2 requires checkpoint kinase ATM activity. DNA repair pathway analysis revealed that HIPK2 depletion specifically impairs HR. Mechanistically, we found that HIPK2 binds BRCA1 and phosphorylates BRCA1 at Ser1191, a site that regulates damage-induced BRCA1 protein stability. Consistently, HIPK2 depletion or pharmacological inhibition of HIPK2 results in reduced BRCA1 protein levels, and sensitizes BRCA1-proficient cancer cells to IR damage and PARPi treatment. In sum, our results identify a role for HIPK2 in HR through regulating BRCA1 protein levels, and propose HIPK2 inhibition as a novel strategy to sensitize BRCA1-proficient cancer cells to PARPi treatment.