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PARP1-specific inhibitor displays PARP1-detrapping activity

Kira Schützenhofer1, Ellen Laker1, Kyle Tsang1

  • 1Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK.

Cell Reports
|May 6, 2026
PubMed

Insights

PARP inhibitors trap PARP1/2 at DNA damage sites, but mutations affect trapping and drug response. This study reveals how specific PARP1 catalytic mutations impact trapping, ADP-ribosylation activity, and sensitivity to PARP inhibitors like saruparib.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Drug Discovery

Background:

  • PARP inhibitors are effective against homologous recombination-deficient tumors by inhibiting PARP1 and PARP2.
  • PARP inhibitor efficacy depends on their ability to trap PARP enzymes at DNA damage sites.
  • Variations in PARP inhibitor trapping ability influence their toxicity.

Purpose of the Study:

  • To investigate the impact of PARP1 catalytic site mutations on its ADP-ribosylation activity, DNA damage trapping, and cellular response to PARP inhibitors.
  • To develop an inducible complementation system for studying PARP1 variants.

Main Methods:

  • Developed an inducible complementation system for expressing tagged PARP1 variants.
  • Assessed ADP-ribosylation activity, PARP trapping, and cell survival of PARP1 mutant cell lines.
  • Tested cell line sensitivity to various PARP inhibitors, including saruparib.

Main Results:

  • Certain PARP1 catalytic mutants showed altered ADP-ribosylation activity and trapping.
  • Saruparib, a PARP1-specific inhibitor, induced release of specific PARP1 catalytic mutants, leading to resistance.
  • Identified a PARP1 mutant with intact mono(ADP-ribosyl)ation but lacking poly(ADP-ribosyl)ation, demonstrating mono(ADP-ribosyl)ation's role in PARP1 release.

Conclusions:

  • PARP1 catalytic site mutations significantly influence PARP trapping and cellular response to PARP inhibitors.
  • Mono(ADP-ribosyl)ation plays a crucial role in the release of PARP1 from DNA damage sites.
  • Understanding these mechanisms can inform the development of more effective PARP inhibitor therapies.
Keywords:
ADP-ribosylationCP: cancerCP: molecular biologyDNA repairPARP inhibitorPARP trappingreplication stress

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