The chromatin remodeler ALC1 underlies resistance to PARP inhibitor treatment.

Autor:	Juhász S; MTA SZBK Lendület DNA Damage and Nuclear Dynamics Research Group, Institute of Genetics, Biological Research Centre, 6276 Szeged, Hungary., Smith R; Univ Rennes, CNRS, IGDR (Institut de Génétique et Développement de Rennes), UMR 6290, BIOSIT, UMS 3480, F-35000 Rennes, France., Schauer T; Biomedical Center, Bioinformatics Unit, Ludwig Maximilian University of Munich, 82152 Planegg-Martinsried, Germany., Spekhardt D; MTA SZBK Lendület DNA Damage and Nuclear Dynamics Research Group, Institute of Genetics, Biological Research Centre, 6276 Szeged, Hungary., Mamar H; MTA SZBK Lendület DNA Damage and Nuclear Dynamics Research Group, Institute of Genetics, Biological Research Centre, 6276 Szeged, Hungary., Zentout S; Univ Rennes, CNRS, IGDR (Institut de Génétique et Développement de Rennes), UMR 6290, BIOSIT, UMS 3480, F-35000 Rennes, France., Chapuis C; Univ Rennes, CNRS, IGDR (Institut de Génétique et Développement de Rennes), UMR 6290, BIOSIT, UMS 3480, F-35000 Rennes, France., Huet S; Univ Rennes, CNRS, IGDR (Institut de Génétique et Développement de Rennes), UMR 6290, BIOSIT, UMS 3480, F-35000 Rennes, France. sebastien.huet@univ-rennes1.fr timinszky.gyula@brc.hu.; Institut Universitaire de France, Paris France., Timinszky G; MTA SZBK Lendület DNA Damage and Nuclear Dynamics Research Group, Institute of Genetics, Biological Research Centre, 6276 Szeged, Hungary. sebastien.huet@univ-rennes1.fr timinszky.gyula@brc.hu.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2020 Dec 18; Vol. 6 (51). Date of Electronic Publication: 2020 Dec 18 (Print Publication: 2020).
DOI:	10.1126/sciadv.abb8626
Abstrakt:	Poly(ADP-ribose) polymerase (PARP) inhibitors are used in the treatment of BRCA-deficient cancers, with treatments currently extending toward other homologous recombination defective tumors. In a genome-wide CRISPR knockout screen with olaparib, we identify ALC1 (Amplified in Liver Cancer 1)-a cancer-relevant poly(ADP-ribose)-regulated chromatin remodeling enzyme-as a key modulator of sensitivity to PARP inhibitor. We found that ALC1 can remove inactive PARP1 indirectly through binding to PARylated chromatin. Consequently, ALC1 deficiency enhances trapping of inhibited PARP1, which then impairs the binding of both nonhomologous end-joining and homologous recombination repair factors to DNA lesions. We also establish that ALC1 overexpression, a common feature in multiple tumor types, reduces the sensitivity of BRCA-deficient cells to PARP inhibitors. Together, we conclude that ALC1-dependent PARP1 mobilization is a key step underlying PARP inhibitor resistance. (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).)
Databáze:	MEDLINE
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