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Nat Commun. 2019 Jul 4;10(1):2954. doi: 10.1038/s41467-019-10741-9.

Poly(ADP-ribose) polymerase-1 antagonizes DNA resection at double-strand breaks.

Author information

1
Genome Stability Laboratory, CHU de Québec Research Center, HDQ Pavilion, Oncology Division, 9 McMahon, Québec City, QC, G1R 3S3, Canada.
2
Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Québec City, QC, G1V 0A6, Canada.
3
Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, 11560 University Avenue, Edmonton, AL, T6G 1Z2, Canada.
4
Department of Molecular Biosciences, University of Texas at Austin, Austin, TX, 78712, USA.
5
CHU de Québec Research Center, CHUL Pavilion, Oncology Division, 2705 Boulevard Laurier, Québec City, QC, G1V 4G2, Canada.
6
Biochemistry and Molecular Medicine, Université de Montréal, 2900 Boulevard Edouard-Montpetit, Pavillon Roger-Gaudry, Montréal, QC, H3T 1J4, Canada.
7
Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, 11560 University Avenue, Edmonton, AL, T6G 1Z2, Canada. mhendzel@ualberta.ca.
8
Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Québec City, QC, G1V 0A6, Canada. guy.poirier@crchudequebec.ulaval.ca.
9
CHU de Québec Research Center, CHUL Pavilion, Oncology Division, 2705 Boulevard Laurier, Québec City, QC, G1V 4G2, Canada. guy.poirier@crchudequebec.ulaval.ca.
10
Genome Stability Laboratory, CHU de Québec Research Center, HDQ Pavilion, Oncology Division, 9 McMahon, Québec City, QC, G1R 3S3, Canada. Jean-Yves.Masson@crchudequebec.ulaval.ca.
11
Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Québec City, QC, G1V 0A6, Canada. Jean-Yves.Masson@crchudequebec.ulaval.ca.

Abstract

PARP-1 is rapidly recruited and activated by DNA double-strand breaks (DSBs). Upon activation, PARP-1 synthesizes a structurally complex polymer composed of ADP-ribose units that facilitates local chromatin relaxation and the recruitment of DNA repair factors. Here, we identify a function for PARP-1 in DNA DSB resection. Remarkably, inhibition of PARP-1 leads to hyperresected DNA DSBs. We show that loss of PARP-1 and hyperresection are associated with loss of Ku, 53BP1 and RIF1 resection inhibitors from the break site. DNA curtains analysis show that EXO1-mediated resection is blocked by PARP-1. Furthermore, PARP-1 abrogation leads to increased DNA resection tracks and an increase of homologous recombination in cellulo. Our results, therefore, place PARP-1 activation as a critical early event for DNA DSB repair activation and regulation of resection. Hence, our work has direct implications for the clinical use and effectiveness of PARP inhibition, which is prescribed for the treatment of various malignancies.

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