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The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin

Dragomir B Krastev1,2, Shudong Li3, Yilun Sun4

  • 1The CRUK Gene Function Laboratory, London, UK.

Nature Cell Biology
|January 11, 2022
PubMed

Insights

Poly (ADP-ribose) polymerase (PARP) inhibitors trap PARP1 in cancer cells. The p97 ATPase processes trapped PARP1, and inhibiting p97 enhances PARP inhibitor effectiveness against tumors.

Area of Science:

  • Molecular biology
  • Cancer research
  • Biochemistry

Background:

  • Poly (ADP-ribose) polymerase (PARP) inhibitors are effective against homologous recombination-defective cancers.
  • PARP inhibitors function by trapping PARP1, a key enzyme, in a chromatin-bound state.
  • The cellular mechanisms for processing trapped PARP1 are not fully understood.

Purpose of the Study:

  • To elucidate the cellular pathways involved in processing trapped PARP1.
  • To identify proteins interacting with trapped PARP1.
  • To explore therapeutic strategies targeting trapped PARP1 processing.

Main Methods:

  • Utilized wild-type and trapping-deficient PARP1 mutants.
  • Employed rapid immunoprecipitation mass spectrometry of endogenous proteins.
  • Applied Apex2 proximity labeling to map protein interactions.

Main Results:

  • Identified an interaction between trapped PARP1 and the p97 ATPase/segregase.
  • Demonstrated that trapped PARP1 undergoes SUMOylation and ubiquitylation, recruiting p97 for chromatin removal.
  • Showed that p97 complex inhibitors, including CuET, prolong PARP1 trapping and enhance anti-cancer effects.

Conclusions:

  • The p97 ATPase is crucial for processing trapped PARP1.
  • Targeting the p97 complex enhances the efficacy of PARP inhibitors in cancer treatment.
  • This study provides a novel therapeutic strategy for homologous recombination-defective cancers.

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