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

Author

Listed:
  • Marie-Christine Caron

    (CHU de Québec Research Center, HDQ Pavilion, Oncology Division
    Laval University Cancer Research Center)

  • Ajit K. Sharma

    (University of Alberta)

  • Julia O’Sullivan

    (CHU de Québec Research Center, HDQ Pavilion, Oncology Division
    Laval University Cancer Research Center)

  • Logan R. Myler

    (University of Texas at Austin)

  • Maria Tedim Ferreira

    (Laval University Cancer Research Center
    CHUL Pavilion, Oncology Division)

  • Amélie Rodrigue

    (CHU de Québec Research Center, HDQ Pavilion, Oncology Division
    Laval University Cancer Research Center)

  • Yan Coulombe

    (CHU de Québec Research Center, HDQ Pavilion, Oncology Division
    Laval University Cancer Research Center)

  • Chantal Ethier

    (Laval University Cancer Research Center
    CHUL Pavilion, Oncology Division)

  • Jean-Philippe Gagné

    (Laval University Cancer Research Center
    CHUL Pavilion, Oncology Division)

  • 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
    CHUL Pavilion, Oncology Division)

  • Jean-Yves Masson

    (CHU de Québec Research Center, HDQ Pavilion, Oncology Division
    Laval University Cancer Research Center)

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.

Suggested Citation

  • 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 & Joh, 2019. "Poly(ADP-ribose) polymerase-1 antagonizes DNA resection at double-strand breaks," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10741-9
    DOI: 10.1038/s41467-019-10741-9
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    Cited by:

    1. Yuandi Gao & Laure Guitton-Sert & Julien Dessapt & Yan Coulombe & Amélie Rodrigue & Larissa Milano & Andréanne Blondeau & Nicolai Balle Larsen & Julien P. Duxin & Samer Hussein & Amélie Fradet-Turcott, 2023. "A CRISPR-Cas9 screen identifies EXO1 as a formaldehyde resistance gene," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    2. Charlotte Blessing & Katja Apelt & Diana Heuvel & Claudia Gonzalez-Leal & Magdalena B. Rother & Melanie Woude & Román González-Prieto & Adi Yifrach & Avital Parnas & Rashmi G. Shah & Tia Tyrsett Kuo &, 2022. "XPC–PARP complexes engage the chromatin remodeler ALC1 to catalyze global genome DNA damage repair," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    3. Susan Kilgas & Aleem Syed & Patrick Toolan-Kerr & Michelle L. Swift & Shrabasti Roychoudhury & Aniruddha Sarkar & Sarah Wilkins & Mikayla Quigley & Anna R. Poetsch & Maria Victoria Botuyan & Gaofeng C, 2024. "NEAT1 modulates the TIRR/53BP1 complex to maintain genome integrity," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    4. Jenny Kaur Singh & Rebecca Smith & Magdalena B. Rother & Anton J. L. Groot & Wouter W. Wiegant & Kees Vreeken & Ostiane D’Augustin & Robbert Q. Kim & Haibin Qian & Przemek M. Krawczyk & Román González, 2021. "Zinc finger protein ZNF384 is an adaptor of Ku to DNA during classical non-homologous end-joining," Nature Communications, Nature, vol. 12(1), pages 1-21, December.
    5. Fen Yang & Jianji Chen & Bin Liu & Guozhen Gao & Manu Sebastian & Collene Jeter & Jianjun Shen & Maria D. Person & Mark T. Bedford, 2021. "SPINDOC binds PARP1 to facilitate PARylation," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    6. Megan E. Luedeman & Susanna Stroik & Wanjuan Feng & Adam J. Luthman & Gaorav P. Gupta & Dale A. Ramsden, 2022. "Poly(ADP) ribose polymerase promotes DNA polymerase theta-mediated end joining by activation of end resection," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    7. Megha Jhanji & Chintada Nageswara Rao & Jacob C. Massey & Marion C. Hope & Xueyan Zhou & C. Dirk Keene & Tao Ma & Michael D. Wyatt & Jason A. Stewart & Mathew Sajish, 2022. "Cis- and trans-resveratrol have opposite effects on histone serine-ADP-ribosylation and tyrosine induced neurodegeneration," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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