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dc.contributor.authorFernando, Madushan
dc.contributor.authorDuijf, Pascal HG
dc.contributor.authorProctor, Martina
dc.contributor.authorStevenson, Alexander J
dc.contributor.authorEhmann, Anna
dc.contributor.authorVora, Shivam
dc.contributor.authorSkalamera, Dubravka
dc.contributor.authorAdams, Mark
dc.contributor.authorGabrielli, Brian
dc.date.accessioned2021-05-24T03:01:51Z
dc.date.available2021-05-24T03:01:51Z
dc.date.issued2021
dc.identifier.issn2157-9024en_US
dc.identifier.doi10.1038/s41389-021-00329-8en_US
dc.identifier.urihttp://hdl.handle.net/10072/404606
dc.description.abstractDefective DNA repair is being demonstrated to be a useful target in cancer treatment. Currently, defective repair is identified by specific gene mutations, however defective repair is a common feature of cancers without these mutations. DNA damage triggers cell cycle checkpoints that are responsible for co-ordinating cell cycle arrest and DNA repair. Defects in checkpoint signalling components such as ataxia telangiectasia mutated (ATM) occur in a low proportion of cancers and are responsible for reduced DNA repair and increased genomic instability. Here we have investigated the AURKA-PLK1 cell cycle checkpoint recovery pathway that is responsible for exit from the G2 phase cell cycle checkpoint arrest. We demonstrate that dysregulation of PP6 and AURKA maintained elevated PLK1 activation to promote premature exit from only ATM, and not ATR-dependent checkpoint arrest. Surprisingly, depletion of the B55α subunit of PP2A that negatively regulates PLK1 was capable of overcoming ATM and ATR checkpoint arrests. Dysregulation of the checkpoint recovery pathway reduced S/G2 phase DNA repair efficiency and increased genomic instability. We found a strong correlation between dysregulation of the PP6-AURKA-PLK1-B55α checkpoint recovery pathway with signatures of defective homologous recombination and increased chromosomal instability in several cancer types. This work has identified an unrealised source of G2 phase DNA repair defects and chromosomal instability that are likely to be sensitive to treatments targeting defective repair.en_US
dc.description.peerreviewedYesen_US
dc.languageengen_US
dc.publisherSpringer Science and Business Media LLCen_US
dc.relation.ispartofpagefrom41en_US
dc.relation.ispartofissue5en_US
dc.relation.ispartofjournalOncogenesisen_US
dc.relation.ispartofvolume10en_US
dc.subject.fieldofresearchBiochemistry and Cell Biologyen_US
dc.subject.fieldofresearchGeneticsen_US
dc.subject.fieldofresearchOncology and Carcinogenesisen_US
dc.subject.fieldofresearchcode0601en_US
dc.subject.fieldofresearchcode0604en_US
dc.subject.fieldofresearchcode1112en_US
dc.titleDysregulated G2 phase checkpoint recovery pathway reduces DNA repair efficiency and increases chromosomal instability in a wide range of tumoursen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Articlesen_US
dcterms.bibliographicCitationFernando, M; Duijf, PHG; Proctor, M; Stevenson, AJ; Ehmann, A; Vora, S; Skalamera, D; Adams, M; Gabrielli, B, Dysregulated G2 phase checkpoint recovery pathway reduces DNA repair efficiency and increases chromosomal instability in a wide range of tumours, Oncogenesis, 2021, 10 (5), pp. 41en_US
dcterms.dateAccepted2021-04-20
dcterms.licensehttps://creativecommons.org/licenses/by/4.0/en_US
dc.date.updated2021-05-21T06:10:45Z
dc.description.versionVersion of Record (VoR)en_US
gro.rights.copyright© The Author(s) 2021. 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.en_US
gro.hasfulltextFull Text
gro.griffith.authorGabrielli, Brian


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