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

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Priyanka Verma1, Yeqiao Zhou2, Zhendong Cao3

  • 1Department of Cancer Biology, Penn Center for Genome Integrity, Basser Center for BRCA, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Nature Cell Biology
|January 19, 2021
PubMed

Insights

The chromatin remodeller ALC1 is crucial for cancer cell survival when homologous recombination is deficient. Its loss dramatically increases sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi), offering a new therapeutic strategy.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • DNA Repair Mechanisms

Background:

  • Response to poly(ADP-ribose) polymerase inhibitors (PARPi) is linked to homologous recombination (HR) DNA repair and PARP enzyme trapping.
  • The role of PARP in chromatin accessibility and its impact on cell viability in PARPi treatment remains largely unexplored.

Purpose of the Study:

  • To investigate whether PARP's role in chromatin accessibility influences cell viability under PARPi treatment.
  • To identify key factors determining PARPi toxicity in homologous recombination-deficient (HRD) cells.

Main Methods:

  • Utilized a CRISPR-based genetic screen to identify determinants of PARPi toxicity.
  • Assessed the impact of ALC1/CHD1L (a PAR-binding chromatin remodeller) on cell viability and PARPi sensitivity in BRCA-mutant cells.
  • Analyzed chromatin accessibility, DNA repair factor association, and DNA damage accumulation.

Main Results:

  • ALC1 was identified as a critical factor for PARPi toxicity in HR-deficient cells.
  • Loss of ALC1 significantly reduced viability and increased PARPi sensitivity (up to 250-fold) in BRCA-mutant cells, overcoming resistance.
  • ALC1 deficiency led to reduced chromatin accessibility, decreased base damage repair factor association, and increased replication-associated DNA damage, enhancing PARP trapping and HR reliance.

Conclusions:

  • PARP-dependent chromatin remodelling is a distinct mechanism influencing PARPi response.
  • ALC1 is a key determinant of PARPi efficacy in HR-deficient cancers.
  • Targeting ALC1-mediated chromatin remodelling presents a potential therapeutic strategy for HR-deficient cancers.

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