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Intrinsic PARG inhibitor sensitivity is mimicked by TIMELESS haploinsufficiency and rescued by nucleoside

Camilla Coulson-Gilmer1, Samantha Littler1, Bethany M Barnes1

  • 1Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester Cancer Research Centre, Wilmslow Road, Manchester M20 4GJ, UK.

NAR Cancer
|July 17, 2024
PubMed

Insights

Cancer cells sensitive to PARG inhibitors can be rescued by nucleoside supplementation, revealing that sensitivity is linked to nucleotide imbalances and not PAR levels. This finding impacts understanding of PARG inhibitor efficacy in cancer therapy.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Biochemistry

Background:

  • A subset of cancer cells exhibit intrinsic sensitivity to poly(ADP-ribose) glycohydrolase (PARG) inhibitors.
  • This sensitivity is associated with persistent DNA replication stress and can be induced by inhibiting TIMELESS, a key replisome accelerator.
  • The underlying vulnerability driving this intrinsic sensitivity remains unclear.

Purpose of the Study:

  • To elucidate the mechanism of PARG inhibitor sensitivity in cancer cells.
  • To investigate the role of nucleotide homeostasis and replisome dynamics in PARG inhibitor response.

Main Methods:

  • Analysis of Timeless model systems and intrinsically sensitive ovarian cancer cells.
  • Assessment of phenotypes associated with PARG inhibitor sensitivity, including replisome speed, fork stalling, S-phase progression, and proliferation.
  • Evaluation of the impact of nucleoside supplementation and thymidylate synthase inhibition on PARG inhibitor sensitivity.

Main Results:

  • Nucleoside supplementation effectively rescued all phenotypes linked to PARG inhibitor sensitivity, restoring proliferation and clonogenic potential.
  • PARG inhibitor resistance was restored by nucleoside supplementation, irrespective of poly(ADP-ribose) chain levels, decoupling sensitivity from PAR levels.
  • Inhibition of thymidylate synthase induced dependency on PARG activity, highlighting the role of dNTP homeostasis.

Conclusions:

  • PARG inhibitor sensitivity in cancer cells is not directly correlated with poly(ADP-ribose) levels.
  • The observed sensitivity likely stems from an impaired ability to manage replisome speed and helicase-polymerase coupling under conditions of nucleotide imbalance.
  • Nucleoside supplementation represents a potential therapeutic strategy to overcome PARG inhibitor resistance by addressing nucleotide deficits.

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