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

Autor:	Blessing C; Department of Physiological Chemistry, Biomedical Center (BMC), Faculty of Medicine, LMU Munich, 82152 Planegg-Martinsried, Germany; International Max Planck Research School (IMPRS) for Molecular Life Sciences, 82152 Planegg-Martinsried, Germany., Mandemaker IK; Department of Physiological Chemistry, Biomedical Center (BMC), Faculty of Medicine, LMU Munich, 82152 Planegg-Martinsried, Germany., Gonzalez-Leal C; Department of Physiological Chemistry, Biomedical Center (BMC), Faculty of Medicine, LMU Munich, 82152 Planegg-Martinsried, Germany; International Max Planck Research School (IMPRS) for Molecular Life Sciences, 82152 Planegg-Martinsried, Germany., Preisser J; Department of Physiological Chemistry, Biomedical Center (BMC), Faculty of Medicine, LMU Munich, 82152 Planegg-Martinsried, Germany., Schomburg A; Department of Physiological Chemistry, Biomedical Center (BMC), Faculty of Medicine, LMU Munich, 82152 Planegg-Martinsried, Germany; Eisbach Bio GmbH, Am Klopferspitz 19, 82152 Planegg-Martinsried, Germany., Ladurner AG; Department of Physiological Chemistry, Biomedical Center (BMC), Faculty of Medicine, LMU Munich, 82152 Planegg-Martinsried, Germany; International Max Planck Research School (IMPRS) for Molecular Life Sciences, 82152 Planegg-Martinsried, Germany; Eisbach Bio GmbH, Am Klopferspitz 19, 82152 Planegg-Martinsried, Germany. Electronic address: andreas.ladurner@bmc.med.lmu.de.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2020 Dec 03; Vol. 80 (5), pp. 862-875.e6.
DOI:	10.1016/j.molcel.2020.10.009
Abstrakt:	The anti-tumor potency of poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) has been linked to trapping of PARP1 on damaged chromatin. However, little is known about their impact on PARP2, an isoform with overlapping functions at DNA lesions. Whether the release of PARP1/2 from DNA lesions is actively catalyzed by molecular machines is also not known. We found that PARPis robustly trap PARP2 and that the helicase ALC1 (CHD1L) is strictly required for PARP2 release. Catalytic inactivation of ALC1 quantitatively traps PARP2 but not PARP1. ALC1 manipulation impacts the response to single-strand DNA breaks through PARP2 trapping, potentiates PARPi-induced cancer cell killing, and mediates synthetic lethality upon BRCA deficiency. The chromatin remodeler ALC1 actively drives PARP2 turnover from DNA lesions, and PARP2 contributes to the cellular responses of PARPi. This suggests that disrupting the ATP-fueled remodeling forces of ALC1 might enable therapies that selectively target the DNA repair functions of PARPs in cancer. Competing Interests: Declaration of Interests A.S. and A.G.L. are co-founders and shareholders of Eisbach Bio, a biotech developing small-molecule inhibitors targeting helicases. (Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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