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Loss of CHTF18-RFC2/5 leads to replicative gaps and sensitivity to PARP inhibitors

Lauryn Buckley-Benbow1, Meryem Ozgencil1, Alessia Tardocchi1,2

  • 1Centre for Cancer Cell & Molecular Biology, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square EC1M 6BQ, London, United Kingdom.

NAR Cancer
|June 5, 2026
PubMed

Insights

Loss of the CHTF18-RFC2/5 complex sensitizes cancer cells to PARP inhibitors (PARPi) by causing replicative gaps. This finding reveals new therapeutic targets for overcoming PARPi resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • PARP inhibitors (PARPi) are vital in treating BRCA1/BRCA2-mutated cancers.
  • Acquired resistance to PARPi presents a significant clinical hurdle.
  • Understanding PARPi sensitivity mechanisms is critical for improving cancer treatment.

Purpose of the Study:

  • To investigate novel mechanisms of PARPi sensitivity.
  • To identify potential therapeutic targets for overcoming PARPi resistance.

Main Methods:

  • CRISPR-Cas9 gene editing to create CHTF18 knockout cells.
  • Analysis of RAD51 foci formation.
  • Assessment of replicative gap accumulation.
  • Transient silencing experiments.
  • Evaluation of 53BP1's role in PARPi sensitivity.

Main Results:

  • Loss of the CHTF18-RFC2/5 complex markedly sensitizes cells to PARPi.
  • CHTF18 deficiency does not impair homologous recombination.
  • PARPi treatment induces replicative gaps in CHTF18 knockout cells.
  • PARP1-PARP2 trapping at replicative gaps is key to PARPi sensitivity.
  • Loss of 53BP1 does not restore PARPi resistance in CHTF18 knockout cells.

Conclusions:

  • The CHTF18-RFC2/5 complex is a novel determinant of PARPi sensitivity.
  • PARP1-PARP2 trapping at replicative gaps drives PARPi sensitivity in CHTF18-deficient cells.
  • Polε and the CHTF18-RFC2/5 complex represent promising therapeutic targets for PARPi-resistant cancers.

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