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The trans cell cycle effects of PARP inhibitors underlie their selectivity toward BRCA1/2-deficient cells

Antoine Simoneau1, Rosalinda Xiong1, Lee Zou1,2

  • 1Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA.

Genes & Development
|August 13, 2021
PubMed

Insights

Poly (ADP-ribose) polymerase inhibitors (PARPi) cause DNA double-strand breaks (DSBs) across cell cycles in BRCA1/2-deficient cells. This progressive DNA damage explains PARPi

Area of Science:

  • Molecular Biology
  • Cancer Therapeutics
  • DNA Repair Mechanisms

Background:

  • Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective against BRCA1/2-deficient tumors.
  • The precise mechanism underlying PARPi's superior efficacy compared to other DNA-damaging agents remains incompletely understood.
  • BRCA1/2 deficiency impairs homologous recombination repair, a critical pathway for resolving DNA damage.

Purpose of the Study:

  • To elucidate the cell cycle-dependent mechanism by which PARPi induces DNA double-strand breaks (DSBs).
  • To investigate why PARPi exhibits unique efficacy in BRCA1/2-deficient cancer cells.

Main Methods:

  • Cellular models of BRCA1/2-deficient and proficient cancers.
  • Treatment with PARP inhibitors (PARPi).
  • Analysis of DNA replication, single-stranded DNA (ssDNA) gap formation, and DNA double-strand break (DSB) induction across cell cycles.
  • Assessment of DNA repair pathway involvement, including ATR and RAD51.
  • Flow cytometry and DNA combing techniques.

Main Results:

  • PARPi induces DNA double-strand breaks (DSBs) predominantly in a trans cell cycle manner.
  • PARPi traps PARP on DNA, leading to single-stranded DNA (ssDNA) gaps that persist until the subsequent S phase.
  • BRCA1/2-deficient cells exhibit increased DSBs due to unrepaired ssDNA gaps, uncontrolled origin firing, and impaired RAD51 recruitment for fork repair.

Conclusions:

  • PARPi triggers progressive DSBs via trans cell cycle ssDNA gaps, overwhelming repair capacity in BRCA1/2-deficient cells.
  • The inability of BRCA1/2-deficient cells to manage accumulating DNA damage across multiple cell cycles underlies the heightened sensitivity to PARPi.
  • This study clarifies the unique therapeutic window of PARPi in BRCA1/2-mutated cancers.
Keywords:
BRCADNA damagePARP inhibitorcell cyclereplication

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