Related Experiment Video

Updated: Jun 18, 2025

Silencing of BRCA2 to Identify Novel BRCA2-regulated Biological Functions in Cultured Human Cells
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Nucleolytic processing of abasic sites underlies PARP inhibitor hypersensitivity in ALC1-deficient BRCA mutant cancer

Natasha Ramakrishnan1, Tyler M Weaver2,3, Lindsey N Aubuchon1,4

  • 1Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, 63110, USA.

Nature Communications
|July 27, 2024
PubMed

Insights

Depleting Amplified in Liver Cancer 1 (ALC1) hypersensitizes cancer cells to poly (ADP-ribose) polymerase inhibitors (PARPi) by impairing abasic site repair. This uncovers a novel mechanism to overcome PARPi resistance and cytotoxicity.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • Clinical use of poly (ADP-ribose) polymerase inhibitors (PARPi) is limited by drug resistance and cytotoxicity.
  • Amplified in Liver Cancer 1 (ALC1) depletion can sensitize BReast CAncer genes 1/2 (BRCA1/2) mutant cells to PARPi.

Purpose of the Study:

  • To investigate the mechanism by which ALC1 depletion overcomes PARPi resistance.
  • To elucidate the role of ALC1 in repairing abasic sites within chromatin.

Main Methods:

  • Cellular assays to assess PARPi sensitivity in ALC1-depleted cells.
  • Biochemical experiments to analyze abasic site processing by Apurinic/Apyrimidinic endonuclease 1 (APE1) in the presence and absence of ALC1.
  • Analysis of DNA replication fork integrity and PARP1/2 trapping.

Main Results:

  • PARPi hypersensitivity in ALC1-deficient cells is dependent on the repair of chromatin-occluded abasic sites.
  • ALC1 facilitates APE1 cleavage of nucleosome-buried abasic sites.
  • In ALC1-deficient cells, unrepaired abasic sites are accessed by APE1 at replication forks, leading to fork breakage and PARP1/2 trapping.

Conclusions:

  • ALC1 plays a critical role in repairing abasic lesions, particularly those shielded by nucleosomes.
  • Cleavage of abasic sites by APE1 is a key mechanism by which cells overcome the chromatin barrier to DNA repair.
  • Targeting ALC1 or related pathways may offer a strategy to enhance PARPi efficacy and overcome treatment resistance in BRCA1/2-mutant cancers.

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