Some cancer treatments target the DNA damage response (DDR) with the goal of avoiding repair of double-strand breaks (DSBs) after genotoxic stress and provoking mitotic failure or lethal aneuploidy in cancer cells. Among DDR-mediating factors, the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is an established key player in DSB repair. Cells lacking DNA-PKcs display profound DSB repair defects, linked to a requirement for DNA-PKcs binding and activation at DSBs to initiate repair through the non-homologous end joining (NHEJ) pathway. In their Research Article, Stephen Kron and colleagues (Liu et al., 2019) challenge the role of DNA-PKcs in DSB repair. They show that inhibition and/or partial knockdown of DNA-PKcs does not prevent timely DSB repair, although γH2AX foci, which are indicative of an active DDR, persisted in breast cancer cells. Mitotic progression of these cells resulted in cytokinesis failure and increased binucleation events. Furthermore, cells with inhibited DNA-PKcs displayed a senescent cell morphology and expression of senescence markers. The authors further demonstrate that downregulation of ataxia telangiectasia mutated kinase (ATM), which has a role in the DDR, suppresses the phenotypes seen in cells with decreased DNA-PKcs. These data separate DNA-PKcs from NHEJ repair and suggest that DNA-PKcs has a role in opposing persistent ATM activity, mitotic slippage and senescence, prompting a re-evaluation of DNA-PKcs as a cancer therapy target.
