ALC1 links chromatin accessibility to PARP inhibitor response in homologous recombination-deficient cells

Nat Cell Biol. 2021 Feb;23(2):160-171. doi: 10.1038/s41556-020-00624-3. Epub 2021 Jan 18.

Abstract

The response to poly(ADP-ribose) polymerase inhibitors (PARPi) is dictated by homologous recombination (HR) DNA repair and the abundance of lesions that trap PARP enzymes. It remains unclear, however, if the established role of PARP in promoting chromatin accessibility impacts viability in these settings. Using a CRISPR-based screen, we identified the PAR-binding chromatin remodeller ALC1/CHD1L as a key determinant of PARPi toxicity in HR-deficient cells. ALC1 loss reduced viability of breast cancer gene (BRCA)-mutant cells and enhanced sensitivity to PARPi by up to 250-fold, while overcoming several resistance mechanisms. ALC1 deficiency reduced chromatin accessibility concomitant with a decrease in the association of base damage repair factors. This resulted in an accumulation of replication-associated DNA damage, increased PARP trapping and a reliance on HR. These findings establish PAR-dependent chromatin remodelling as a mechanistically distinct aspect of PARPi responses and therapeutic target in HR-deficient cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • BRCA1 Protein / genetics
  • BRCA2 Protein / genetics
  • CRISPR-Cas Systems / genetics
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Chromatin / metabolism*
  • Chromatin Assembly and Disassembly / drug effects
  • Chromosome Aberrations
  • DNA Helicases / chemistry
  • DNA Helicases / metabolism*
  • DNA Repair / drug effects
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / metabolism*
  • Epistasis, Genetic / drug effects
  • Genomic Instability
  • Green Fluorescent Proteins / metabolism
  • Homologous Recombination / drug effects
  • Homologous Recombination / genetics*
  • Humans
  • Methyl Methanesulfonate
  • Mutation / genetics
  • Phthalazines / pharmacology
  • Piperazines / pharmacology
  • Poly Adenosine Diphosphate Ribose / metabolism
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Protein Domains

Substances

  • BRCA1 Protein
  • BRCA2 Protein
  • Chromatin
  • DNA-Binding Proteins
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Green Fluorescent Proteins
  • Poly Adenosine Diphosphate Ribose
  • Methyl Methanesulfonate
  • Poly(ADP-ribose) Polymerases
  • DNA Helicases
  • CHD1L protein, human
  • olaparib