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Clinical PARP inhibitors allosterically induce PARP2 retention on DNA

Marie-France Langelier1, Xiaohui Lin2, Shan Zha2

  • 1Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC H3C 3J7, Canada.

Science Advances
|March 24, 2023
PubMed

Insights

Certain PARP inhibitors (PARPi) unexpectedly retain PARP2 on DNA breaks through an allosteric mechanism, unlike their effect on PARP1. This finding aids in understanding PARPi toxicity and developing improved cancer therapies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Poly(ADP-ribose) polymerases (PARP1 and PARP2) are crucial for DNA break detection and repair.
  • PARP inhibitors (PARPi) are established cancer treatments targeting PARP catalytic activity, leading to increased DNA damage persistence.
  • Some PARPi can allosterically increase PARP1 retention on DNA, but this has not been observed for PARP1 with clinical agents.

Purpose of the Study:

  • To investigate the allosteric effects of clinical PARP inhibitors (PARPi) on PARP2.
  • To elucidate the mechanism by which PARPi interact with PARP2 at DNA breaks.
  • To explore the implications of these interactions for PARPi efficacy and toxicity.

Main Methods:

  • Utilized a PARP2 mutant mimicking allosteric inhibitor effects to assess DNA retention.
  • Investigated the impact of the clinical PARPi AZD5305 on PARP2 behavior at DNA damage sites.
  • Analyzed the communication between catalytic and DNA-binding regions of PARP2.

Main Results:

  • Demonstrated that certain clinical PARPi induce an allosteric effect that retains PARP2 on DNA breaks.
  • Showed this PARP2 retention is dependent on communication between its catalytic and DNA-binding domains.
  • Observed increased PARP2 retention at cellular damage sites using a PARP2 mutant and AZD5305.

Conclusions:

  • Clinical PARPi can exert a reverse allosteric effect on PARP2, retaining it on DNA.
  • This PARP2 retention mechanism may contribute to the observed toxicity of current PARPi.
  • Findings provide a basis for designing next-generation PARPi with improved therapeutic profiles.

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