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

Luc Provencher1, Wilson Nartey1, Peter M Brownlee1

  • 1Robson DNA Science Centre, Charbonneau Cancer Institute, Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Nature Communications
|January 25, 2025
PubMed

Insights

Mutating the CHD6 chromatin remodeler sensitizes cells to PARP1/2 inhibitors, distinct from BRCA1. CHD6 loss impairs DNA repair, increasing sensitivity to replication stress and PARP1/2-trapping inhibitors.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Poly(ADP-ribose) (PAR) polymerase 1 and 2 (PARP1/2) inhibitors are effective cancer treatments, particularly for BRCA1/2-deficient cancers, by targeting DNA repair.
  • Oxidative stress response involves DNA repair mechanisms that can be modulated by PARP1/2 activity.

Purpose of the Study:

  • To investigate the role of the CHD6 chromatin remodeler in cellular response to PARP1/2 inhibition.
  • To elucidate the mechanism by which CHD6 influences sensitivity to PARP1/2 inhibitors and replication stress.

Main Methods:

  • Genetic mutation of the CHD6 chromatin remodeler.
  • Assessment of cellular sensitivity to PARP1/2 inhibitors and replication stress.
  • Analysis of DNA damage response pathways, including RAD51 foci formation and γH2AX accumulation.
  • Investigation of CHD6 protein interactions and localization to DNA damage sites.
  • DNA repair pathway screening and assessment of apurinic-apyrimidinic endonuclease (APEX1) activity.

Main Results:

  • Mutating CHD6 sensitizes cells to PARP1/2 inhibitors through a mechanism distinct from BRCA1.
  • CHD6 recruitment to DNA damage requires its PAR- and DNA-binding domains, crucial for nucleosome sliding.
  • CHD6 loss does not affect RAD51 foci or double-strand break repair but increases sensitivity to replication stress.
  • CHD6 deficiency leads to accumulation of abasic sites due to impaired APEX1 activity, exacerbating sensitivity to PARP1/2-trapping agents.

Conclusions:

  • CHD6 plays a critical role in DNA repair and tolerance to replication stress.
  • CHD6's interaction with PARP1/2 and its role in APEX1 activity are key determinants of sensitivity to PARP1/2-trapping inhibitors.
  • Targeting CHD6 or understanding its pathways could offer new therapeutic strategies for cancers, particularly those resistant to current treatments.

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