Journal article
The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
Actions
Access Document
- Files:
-
-
(Preview, Version of record, 11.6MB, Terms of use)
-
- Publisher copy:
- 10.1038/s41556-021-00807-6
Authors
- Publisher:
- Springer Nature
- Journal:
- Nature Cell Biology More from this journal
- Volume:
- 24
- Issue:
- 1
- Pages:
- 62-73
- Publication date:
- 2022-01-10
- Acceptance date:
- 2021-11-03
- DOI:
- EISSN:
-
1476-4679
- ISSN:
-
1465-7392
- Pmid:
-
35013556
- Language:
-
English
- Keywords:
- Pubs id:
-
1231620
- Local pid:
-
pubs:1231620
- Deposit date:
-
2022-04-23
Terms of use
- Copyright holder:
- Krastev et al
- Copyright date:
- 2022
- Rights statement:
- © The Author(s) 2022. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
If you are the owner of this record, you can report an update to it here: Report update to this record