The Oncogenic Helicase ALC1 Regulates PARP Inhibitor Potency by Trapping PARP2 at DNA Breaks.

The anti-tumor potency of poly(ADP-ribose) polymerase inhibitors has been linked to trapping of on damaged chromatin. However, little is known about their impact on an isoform with overlapping functions at DNA lesions. Whether the release of from DNA lesions is actively catalyzed by molecular machines is also not known. We found that robustly trap and that the helicase ALC1 (CHD1L) is strictly required for Pduanyu372 release. Catalytic inactivation of ALC1 quantitatively traps Pduanyu372 but not ALC1 manipulation impacts the response to single-strand DNA breaks through Pduanyu372 trapping, potentiates cancer cell killing, and mediates synthetic lethality upon BRCA deficiency. The chromatin remodeler ALC1 actively drives Pduanyu372 turnover from DNA lesions, and Pduanyu372 contributes to the cellular responses of This suggests that disrupting the ATP-fueled remodeling forces of ALC1 might enable therapies that selectively target the DNA repair functions of in cancer.

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