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dc.contributor.authorBalmus, Gabrielen
dc.contributor.authorPilger, Domenicen
dc.contributor.authorCoates, Juliaen
dc.contributor.authorDemir, Mukerremen
dc.contributor.authorSczaniecka-Clift, Matyldaen
dc.contributor.authorBarros, Ana Cen
dc.contributor.authorWoods, Michaelen
dc.contributor.authorFu, Beiyuanen
dc.contributor.authorYang, Fengtangen
dc.contributor.authorChen, Elisabethen
dc.contributor.authorOstermaier, Matthiasen
dc.contributor.authorStankovic, Tatjanaen
dc.contributor.authorPonstingl, Hannesen
dc.contributor.authorHerzog, Mareikeen
dc.contributor.authorYusa, Kosukeen
dc.contributor.authorMartinez, Francisco Munozen
dc.contributor.authorDurant, Stephen Ten
dc.contributor.authorGalanty, Yaronen
dc.contributor.authorBeli, Petraen
dc.contributor.authorAdams, David Jen
dc.contributor.authorBradley, Allanen
dc.contributor.authorMetzakopian, Emmanouilen
dc.contributor.authorForment, Josepen
dc.contributor.authorJackson, Stephenen
dc.date.accessioned2019-01-18T00:31:45Z
dc.date.available2019-01-18T00:31:45Z
dc.date.issued2019-01-08en
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/288189
dc.description.abstractMutations in the ATM tumor suppressor confer hypersensitivity to DNA-damaging agents. To explore genetic resistance mechanisms, we performed genome-wide CRISPR-Cas9 screens in cells treated with the DNA topoisomerase poison topotecan. Thus, we here establish that inactivating terminal components of the non-homologous end-joining (NHEJ) machinery or the BRCA1-A complex specifically confers topotecan resistance to ATM-deficient cells. We show that hypersensitivity of ATM-mutant cells to topotecan or the poly-(ADP-ribose) polymerase (PARP) inhibitor olaparib reflects delayed engagement of homologous recombination at DNA-replication-fork associated single-ended double-strand breaks (DSBs), allowing some to be subject to toxic NHEJ. Preventing DSB ligation by NHEJ, or enhancing homologous recombination by BRCA1-A complex disruption, suppresses this toxicity, highlighting a crucial role for ATM in preventing toxic LIG4-mediated chromosome fusions. Notably, suppressor mutations in ATM-mutant backgrounds are different to those in BRCA1-mutant scenarios, suggesting new opportunities for patient stratification and additional therapeutic vulnerabilities for clinical exploitation.
dc.format.mediumElectronicen
dc.languageengen
dc.publisherSpringer Nature
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectCell Line, Tumoren
dc.subjectAnimalsen
dc.subjectMice, Inbred NODen
dc.subjectMice, Knockouten
dc.subjectHumansen
dc.subjectMiceen
dc.subjectNeoplasms, Experimentalen
dc.subjectTopotecanen
dc.subjectPiperazinesen
dc.subjectPhthalazinesen
dc.subjectBRCA1 Proteinen
dc.subjectAntineoplastic Agentsen
dc.subjectCell Survivalen
dc.subjectDNA Replicationen
dc.subjectDrug Resistance, Neoplasmen
dc.subjectMutationen
dc.subjectFemaleen
dc.subjectDNA Breaks, Double-Strandeden
dc.subjectDNA End-Joining Repairen
dc.subjectAtaxia Telangiectasia Mutated Proteinsen
dc.subjectCRISPR-Cas Systemsen
dc.subjectMouse Embryonic Stem Cellsen
dc.subjectDNA Ligase ATPen
dc.titleATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks.en
dc.typeArticle
prism.issueIdentifier1en
prism.publicationDate2019en
prism.publicationNameNature communicationsen
prism.startingPage87
prism.volume10en
dc.identifier.doi10.17863/CAM.35505
dcterms.dateAccepted2018-11-15en
rioxxterms.versionofrecord10.1038/s41467-018-07729-2en
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2019-01-08en
dc.contributor.orcidBalmus, Gabriel [0000-0003-2872-4468]
dc.contributor.orcidPilger, Domenic [0000-0001-7339-0685]
dc.contributor.orcidYang, Fengtang [0000-0002-3573-2354]
dc.contributor.orcidChen, Elisabeth [0000-0003-2129-7985]
dc.contributor.orcidStankovic, Tatjana [0000-0002-3780-274X]
dc.contributor.orcidPonstingl, Hannes [0000-0001-7573-1703]
dc.contributor.orcidHerzog, Mareike [0000-0001-9747-2327]
dc.contributor.orcidDurant, Stephen T [0000-0003-4209-7499]
dc.contributor.orcidGalanty, Yaron [0000-0001-7167-9004]
dc.contributor.orcidBeli, Petra [0000-0001-9507-9820]
dc.contributor.orcidBradley, Allan [0000-0002-2349-8839]
dc.contributor.orcidForment, Josep [0000-0002-7797-2583]
dc.contributor.orcidJackson, Stephen [0000-0001-9317-7937]
dc.identifier.eissn2041-1723
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idCancer Research UK (11224)
pubs.funder-project-idCancer Research UK (A18796)
pubs.funder-project-idWellcome Trust (206388/Z/17/Z)
pubs.funder-project-idCancer Research UK (C6/A21454)
pubs.funder-project-idCancer Research UK (C6946/A24843)
pubs.funder-project-idWellcome Trust (203144/Z/16/Z)


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International