The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin.
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Authors
Krastev, DB
Li, S
Sun, Y
Wicks, AJ
Hoslett, G
Weekes, D
Badder, LM
Knight, EG
Marlow, R
Pardo, MC
Yu, L
Talele, TT
Bartek, J
Choudhary, JS
Pommier, Y
Pettitt, SJ
Tutt, ANJ
Ramadan, K
Lord, CJ
Li, S
Sun, Y
Wicks, AJ
Hoslett, G
Weekes, D
Badder, LM
Knight, EG
Marlow, R
Pardo, MC
Yu, L
Talele, TT
Bartek, J
Choudhary, JS
Pommier, Y
Pettitt, SJ
Tutt, ANJ
Ramadan, K
Lord, CJ
Document Type
Journal Article
Date
2022-01-01
Date Accepted
2021-11-03
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.
Citation
Nature Cell Biology
Source Title
Publisher
NATURE PORTFOLIO
ISSN
1465-7392
eISSN
1476-4679
1476-4679
1476-4679
Research Team
Functional Proteomics Group
Gene Function
Gene Function