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PARG-deficient tumor cells have an increased dependence on EXO1/FEN1-mediated DNA repair

Christina Andronikou1,2,3,4, Kamila Burdova5, Diego Dibitetto1,4

  • 1Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, 3012, Bern, Switzerland.

The EMBO Journal
|February 15, 2024
PubMed

Insights

Targeting poly(ADP-ribose) glycohydrolase (PARG) uncovers new vulnerabilities in cancer cells. Inhibiting EXO1/FEN1 shows promise for treating PARPi-resistant and BRCA2-deficient tumors.

Area of Science:

  • Genetics
  • Cancer Biology
  • DNA Repair

Background:

  • Poly(ADP-ribose) glycohydrolase (PARG) inhibition is a potential cancer therapy.
  • Understanding genetic vulnerabilities is crucial for PARG-targeted treatments.
  • PARG loss can cause resistance to PARP inhibitors (PARPi) in BRCA2;p53-deficient tumors.

Purpose of the Study:

  • Identify genetic vulnerabilities in PARG-deficient cancer cells.
  • Explore synthetic lethal interactions with PARG loss.
  • Investigate therapeutic strategies for PARPi-resistant and homologous recombination-deficient tumors.

Main Methods:

  • Whole-genome CRISPR/Cas9 drop-out screens were performed.
  • Assessed the essentiality of DNA repair genes in PARG;BRCA2;p53-deficient cells.
  • Analyzed replication fork progression, DNA single-strand break repair, and Okazaki fragment processing.

Main Results:

  • EXO1 and FEN1 were identified as major synthetic lethal interactors of PARG loss.
  • PARG;BRCA2;p53-deficient cells exhibit compromised DNA repair pathways.
  • Inhibition of EXO1/FEN1 is lethal in the context of PARG loss and BRCA2 deficiency.

Conclusions:

  • EXO1/FEN1 targeting is a viable strategy for PARPi-resistant tumors with PARG loss.
  • Targeting EXO1/FEN1 can enhance PARG inhibitor efficacy in homologous recombination-deficient cancers.
  • This study reveals critical DNA repair vulnerabilities associated with PARG deficiency.
Keywords:
BRCA2DNA RepairEXO1FEN1PARG

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