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The chromatin remodeler ALC1 underlies resistance to PARP inhibitor treatment

Szilvia Juhász1, Rebecca Smith2, Tamás Schauer3

  • 1MTA SZBK Lendület DNA Damage and Nuclear Dynamics Research Group, Institute of Genetics, Biological Research Centre, 6276 Szeged, Hungary.

Science Advances
|December 23, 2020
PubMed

Insights

Amplified in Liver Cancer 1 (ALC1) removes inactive PARP1, influencing cancer drug sensitivity. ALC1 overexpression reduces sensitivity to PARP inhibitors in BRCA-deficient cancers, revealing a resistance mechanism.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Poly(ADP-ribose) polymerase (PARP) inhibitors are crucial for treating BRCA-deficient and other homologous recombination defective cancers.
  • Understanding resistance mechanisms to PARP inhibitors is vital for improving cancer therapy.

Purpose of the Study:

  • To identify novel modulators of sensitivity to PARP inhibitors.
  • To investigate the role of Amplified in Liver Cancer 1 (ALC1) in PARP inhibitor response and resistance.

Main Methods:

  • Genome-wide CRISPR knockout screen using olaparib.
  • Assays to assess the interaction of ALC1 with PARP1 and chromatin.
  • Evaluation of DNA repair factor binding to DNA lesions in ALC1-deficient and overexpressing cells.

Main Results:

  • ALC1 was identified as a key modulator of sensitivity to PARP inhibitors.
  • ALC1 removes inactive PARP1 from PARylated chromatin.
  • ALC1 deficiency enhances PARP1 trapping, impairing DNA repair factor binding.
  • ALC1 overexpression reduces sensitivity to PARP inhibitors in BRCA-deficient cells.

Conclusions:

  • ALC1-dependent mobilization of PARP1 is a critical mechanism of resistance to PARP inhibitors.
  • Targeting ALC1 could potentially overcome PARP inhibitor resistance in certain cancers.
  • ALC1's role in chromatin remodeling impacts DNA repair and drug sensitivity.

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