dc.contributor.author | Krastev, DB | |
dc.contributor.author | Li, S | |
dc.contributor.author | Sun, Y | |
dc.contributor.author | Wicks, AJ | |
dc.contributor.author | Hoslett, G | |
dc.contributor.author | Weekes, D | |
dc.contributor.author | Badder, LM | |
dc.contributor.author | Knight, EG | |
dc.contributor.author | Marlow, R | |
dc.contributor.author | Pardo, MC | |
dc.contributor.author | Yu, L | |
dc.contributor.author | Talele, TT | |
dc.contributor.author | Bartek, J | |
dc.contributor.author | Choudhary, JS | |
dc.contributor.author | Pommier, Y | |
dc.contributor.author | Pettitt, SJ | |
dc.contributor.author | Tutt, ANJ | |
dc.contributor.author | Ramadan, K | |
dc.contributor.author | Lord, CJ | |
dc.date.accessioned | 2022-01-18T15:00:47Z | |
dc.date.available | 2022-01-18T15:00:47Z | |
dc.date.issued | 2022-01-01 | |
dc.identifier.citation | Nature Cell Biology | |
dc.identifier.issn | 1465-7392 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4963 | |
dc.identifier.eissn | 1476-4679 | |
dc.identifier.eissn | 1476-4679 | |
dc.identifier.doi | 10.1038/s41556-021-00807-6 | |
dc.identifier.doi | 10.1038/s41556-021-00807-6 | |
dc.description.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. | |
dc.language | en | |
dc.language.iso | eng | |
dc.publisher | NATURE PORTFOLIO | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.title | The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2021-11-03 | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1038/s41556-021-00807-6 | |
dc.relation.isPartOf | Nature Cell Biology | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/ImmNet | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Functional Proteomics Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
pubs.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/20/21 Starting Cohort | |
pubs.publication-status | Published online | |
pubs.embargo.terms | Not known | |
icr.researchteam | Functional Proteomics Group | |
icr.researchteam | Gene Function | |
dc.contributor.icrauthor | Krastev, Dragomir | |
dc.contributor.icrauthor | Wicks, Andrew | |
dc.contributor.icrauthor | Pardo Calvo, Maria Mercedes | |
dc.contributor.icrauthor | Choudhary, Jyoti | |
dc.contributor.icrauthor | Pettitt, Stephen | |
dc.contributor.icrauthor | Tutt, Andrew | |
dc.contributor.icrauthor | Lord, Christopher | |