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

Marie-Christine Caron, Ajit K. Sharma, Julia O’Sullivan, Logan R. Myler, Maria Tedim Ferreira, Amélie Rodrigue, Yan Coulombe, Chantal Ethier, Jean-Philippe Gagné, Marie-France Langelier, John M. Pascal, Ilya J. Finkelstein, Michael J. Hendzel (), Guy G. Poirier () and Jean-Yves Masson ()
Additional contact information
Marie-Christine Caron: CHU de Québec Research Center, HDQ Pavilion, Oncology Division
Ajit K. Sharma: University of Alberta
Julia O’Sullivan: CHU de Québec Research Center, HDQ Pavilion, Oncology Division
Logan R. Myler: University of Texas at Austin
Maria Tedim Ferreira: Laval University Cancer Research Center
Amélie Rodrigue: CHU de Québec Research Center, HDQ Pavilion, Oncology Division
Yan Coulombe: CHU de Québec Research Center, HDQ Pavilion, Oncology Division
Chantal Ethier: Laval University Cancer Research Center
Jean-Philippe Gagné: Laval University Cancer Research Center
Marie-France Langelier: Université de Montréal
John M. Pascal: Université de Montréal
Ilya J. Finkelstein: University of Texas at Austin
Michael J. Hendzel: University of Alberta
Guy G. Poirier: Laval University Cancer Research Center
Jean-Yves Masson: CHU de Québec Research Center, HDQ Pavilion, Oncology Division

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10741-9

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