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

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

Research output: Contribution to journalArticlepeer-review

61 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)62-73
Number of pages12
JournalNature Cell Biology
Volume24
Issue number1
Early online date10 Jan 2022
DOIs
Publication statusPublished - 10 Jan 2022

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