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CHD6 has poly(ADP-ribose)- and DNA-binding domains and regulates PARP1/2-trapping inhibitor sensitivity via abasic site repair

Author

Listed:
  • Luc Provencher

    (University of Calgary)

  • Wilson Nartey

    (University of Calgary)

  • Peter M. Brownlee

    (University of Calgary)

  • Austin W. Atkins

    (University of Calgary)

  • Jean-Philippe Gagné

    (Laval University Cancer Research Center
    CHU de Québec Research Center)

  • Lou Baudrier

    (University of Calgary)

  • Nicholas S. Y. Ting

    (University of Calgary)

  • Cortt G. Piett

    (School of Public Health)

  • Shujuan Fang

    (University of Calgary)

  • Dustin D. Pearson

    (University of Calgary)

  • Shaun Moore

    (University of Calgary)

  • Pierre Billon

    (University of Calgary)

  • Zachary D. Nagel

    (School of Public Health)

  • Guy G. Poirier

    (Laval University Cancer Research Center
    CHU de Québec Research Center)

  • Gareth J. Williams

    (University of Calgary)

  • Aaron A. Goodarzi

    (University of Calgary)

Abstract

To tolerate oxidative stress, cells enable DNA repair responses often sensitive to poly(ADP-ribose) (PAR) polymerase 1 and 2 (PARP1/2) inhibition—an intervention effective against cancers lacking BRCA1/2. Here, we demonstrate that mutating the CHD6 chromatin remodeler sensitizes cells to PARP1/2 inhibitors in a manner distinct from BRCA1, and that CHD6 recruitment to DNA damage requires cooperation between PAR- and DNA-binding domains essential for nucleosome sliding activity. CHD6 displays direct PAR-binding, interacts with PARP-1 and other PAR-associated proteins, and combined DNA- and PAR-binding loss eliminates CHD6 relocalization to DNA damage. While CHD6 loss does not impair RAD51 foci formation or DNA double-strand break repair, it causes sensitivity to replication stress, and PARP1/2-trapping or Pol ζ inhibitor-induced γH2AX foci accumulation in S-phase. DNA repair pathway screening reveals that CHD6 loss elicits insufficiency in apurinic-apyrimidinic endonuclease (APEX1) activity and genomic abasic site accumulation. We reveal APEX1-linked roles for CHD6 important for understanding PARP1/2-trapping inhibitor sensitivity.

Suggested Citation

  • Luc Provencher & Wilson Nartey & Peter M. Brownlee & Austin W. Atkins & Jean-Philippe Gagné & Lou Baudrier & Nicholas S. Y. Ting & Cortt G. Piett & Shujuan Fang & Dustin D. Pearson & Shaun Moore & Pie, 2025. "CHD6 has poly(ADP-ribose)- and DNA-binding domains and regulates PARP1/2-trapping inhibitor sensitivity via abasic site repair," Nature Communications, Nature, vol. 16(1), pages 1-24, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56085-5
    DOI: 10.1038/s41467-025-56085-5
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    References listed on IDEAS

    as
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