The binding of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to Ku proteins at DNA double strand breaks (DSBs) has long been considered essential for non-homologous end joining (NHEJ) repair, providing a rationale for DNA-PKcs inhibitors as cancer therapeutics. Given lagging clinical translation, we reexamined mechanisms and observed instead that DSB repair can proceed independently of DNA-PKcs. While repair of radiation-induced DSBs was blocked in cells expressing shRNAs targeting Ku proteins or other NHEJ core factors, DSBs were repaired on schedule despite targeting DNA-PKcs. Although we failed to observe a DSB repair defect, γH2AX foci persisted indefinitely after irradiation, leading to cytokinesis failure and accumulation of binucleated cells. Following this mitotic slippage, cells with decreased DNA-PKcs underwent accelerated senescence. We identified down-regulation of ataxia-telangiectasia mutated kinase (ATM) as the critical role for DNA-PKcs in recovery from DNA damage insofar as targeting ATM restored γH2AX foci resolution and cytokinesis. Considering the lack of direct impact on DSB repair and emerging links between senescence and therapy resistance, these results suggest reassessing DNA-PKcs as a cancer target.
Repair-independent functions of DNA-PKcs protect irradiated cells from mitotic slippage and accelerated senescence
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Yue Liu, Elena V. Efimova, Aishwarya Ramamurthy, Stephen J. Kron; Repair-independent functions of DNA-PKcs protect irradiated cells from mitotic slippage and accelerated senescence. J Cell Sci 2019; jcs.229385. doi: https://doi.org/10.1242/jcs.229385
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