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dc.contributor.authorKrastev, DB
dc.contributor.authorLi, S
dc.contributor.authorSun, Y
dc.contributor.authorWicks, AJ
dc.contributor.authorHoslett, G
dc.contributor.authorWeekes, D
dc.contributor.authorBadder, LM
dc.contributor.authorKnight, EG
dc.contributor.authorMarlow, R
dc.contributor.authorPardo, MC
dc.contributor.authorYu, L
dc.contributor.authorTalele, TT
dc.contributor.authorBartek, J
dc.contributor.authorChoudhary, JS
dc.contributor.authorPommier, Y
dc.contributor.authorPettitt, SJ
dc.contributor.authorTutt, ANJ
dc.contributor.authorRamadan, K
dc.contributor.authorLord, CJ
dc.date.accessioned2022-01-18T15:00:47Z
dc.date.available2022-01-18T15:00:47Z
dc.identifier.citationNature Cell Biologyen_US
dc.identifier.issn1465-7392
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4963
dc.identifier.eissn1476-4679en_US
dc.identifier.eissn1476-4679
dc.identifier.doi10.1038/s41556-021-00807-6en_US
dc.identifier.doi10.1038/s41556-021-00807-6
dc.description.abstract<jats:title>Abstract</jats:title><jats:p>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.</jats:p>en_US
dc.languageenen_US
dc.language.isoengen_US
dc.publisherSpringer Science and Business Media LLCen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titleThe ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatinen_US
dc.typeJournal Article
dcterms.dateAccepted2021-11-03
rioxxterms.versionVoRen_US
rioxxterms.versionofrecord10.1038/s41556-021-00807-6en_US
dc.relation.isPartOfNature Cell Biologyen_US
pubs.notesNot knownen_US
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-statusPublished onlineen_US
pubs.embargo.termsNot knownen_US
icr.researchteamFunctional Proteomics Group
icr.researchteamGene Function
dc.contributor.icrauthorWicks, Andrewen_US
dc.contributor.icrauthorLord, Christopheren_US
dc.contributor.icrauthorPettitt, Stephenen_US
dc.contributor.icrauthorKrastev, Dragomiren_US
dc.contributor.icrauthorTutt, Andrewen_US
dc.contributor.icrauthorChoudhary, Jyotien_US
dc.contributor.icrauthorPardo Calvo, Maria Mercedesen_US


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