The Ubiquitin-dependent ATPase P97 Removes Cytotoxic Trapped PARP1 from Chromatin

Overview

Journal Nat Cell Biol

Specialty Cell Biology

Date 2022 Jan 11

PMID 35013556

Authors

Dragomir B Krastev

Shudong Li

Yilun Sun

Andrew J Wicks

Gwendoline Hoslett

Daniel Weekes

Luned M Badder

Eleanor G Knight

Rebecca Marlow

Mercedes Calvo Pardo

Lu Yu

Tanaji T Talele

Jiri Bartek

Jyoti S Choudhary

Yves Pommier

Stephen J Pettitt

Andrew N J Tutt

Kristijan Ramadan

Christopher J Lord

Affiliations

Soon will be listed here.

Abstract

Poly (ADP-ribose) polymerase (PARP) inhibitors elicit antitumour activity in homologous recombination-defective cancers by trapping PARP1 in a chromatin-bound state. How cells process trapped PARP1 remains unclear. Using wild-type and a trapping-deficient PARP1 mutant combined with rapid immunoprecipitation mass spectrometry of endogenous proteins and Apex2 proximity labelling, we delineated mass spectrometry-based interactomes of trapped and non-trapped PARP1. These analyses identified an interaction between trapped PARP1 and the ubiquitin-regulated p97 ATPase/segregase. We found that following trapping, PARP1 is SUMOylated by PIAS4 and subsequently ubiquitylated by the SUMO-targeted E3 ubiquitin ligase RNF4, events that promote recruitment of p97 and removal of trapped PARP1 from chromatin. Small-molecule p97-complex inhibitors, including a metabolite of the clinically used drug disulfiram (CuET), prolonged PARP1 trapping and enhanced PARP inhibitor-induced cytotoxicity in homologous recombination-defective tumour cells and patient-derived tumour organoids. Together, these results suggest that p97 ATPase plays a key role in the processing of trapped PARP1 and the response of tumour cells to PARP inhibitors.

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