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

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, Pierre Billon, Zachary D. Nagel, Guy G. Poirier, Gareth J. Williams () and Aaron A. Goodarzi ()
Additional contact information
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
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
Gareth J. Williams: University of Calgary
Aaron A. Goodarzi: University of Calgary

Nature Communications, 2025, vol. 16, issue 1, 1-24

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56085-5

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