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ATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks.

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cam.issuedOnline2019-01-08
dc.contributor.authorBalmus, Gabriel
dc.contributor.authorPilger, Domenic
dc.contributor.authorCoates, Julia
dc.contributor.authorDemir, Mukerrem
dc.contributor.authorSczaniecka-Clift, Matylda
dc.contributor.authorBarros, Ana C
dc.contributor.authorWoods, Michael
dc.contributor.authorFu, Beiyuan
dc.contributor.authorYang, Fengtang
dc.contributor.authorChen, Elisabeth
dc.contributor.authorOstermaier, Matthias
dc.contributor.authorStankovic, Tatjana
dc.contributor.authorPonstingl, Hannes
dc.contributor.authorHerzog, Mareike
dc.contributor.authorYusa, Kosuke
dc.contributor.authorMartinez, Francisco Munoz
dc.contributor.authorDurant, Stephen T
dc.contributor.authorGalanty, Yaron
dc.contributor.authorBeli, Petra
dc.contributor.authorAdams, David J
dc.contributor.authorBradley, Allan
dc.contributor.authorMetzakopian, Emmanouil
dc.contributor.authorForment, Josep V
dc.contributor.authorJackson, Stephen P
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.orcidPonstingl, Hannes [0000-0001-7573-1703]
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.orcidForment, Josep V [0000-0002-7797-2583]
dc.contributor.orcidJackson, Stephen P [0000-0001-9317-7937]
dc.date.accessioned2019-01-18T00:31:45Z
dc.date.available2019-01-18T00:31:45Z
dc.date.issued2019-01-08
dc.description.abstractMutations in the ATM tumor suppressor gene confer hypersensitivity to DNA-damaging chemotherapeutic agents. To explore genetic resistance mechanisms, we performed genome-wide CRISPR-Cas9 screens in cells treated with the DNA topoisomerase I inhibitor topotecan. Thus, we here establish that inactivating terminal components of the non-homologous end-joining (NHEJ) machinery or of the BRCA1-A complex specifically confer 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.mediumElectronic
dc.identifier.doi10.17863/CAM.35505
dc.identifier.eissn2041-1723
dc.identifier.issn2041-1723
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/288189
dc.languageeng
dc.language.isoeng
dc.publisherSpringer Science and Business Media LLC
dc.publisher.urlhttp://dx.doi.org/10.1038/s41467-018-07729-2
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAnimals
dc.subjectAntineoplastic Agents
dc.subjectAtaxia Telangiectasia Mutated Proteins
dc.subjectBRCA1 Protein
dc.subjectCRISPR-Cas Systems
dc.subjectCell Line, Tumor
dc.subjectCell Survival
dc.subjectDNA Breaks, Double-Stranded
dc.subjectDNA End-Joining Repair
dc.subjectDNA Ligase ATP
dc.subjectDNA Replication
dc.subjectDrug Resistance, Neoplasm
dc.subjectFemale
dc.subjectHumans
dc.subjectMice
dc.subjectMice, Inbred NOD
dc.subjectMice, Knockout
dc.subjectMouse Embryonic Stem Cells
dc.subjectMutation
dc.subjectNeoplasms, Experimental
dc.subjectPhthalazines
dc.subjectPiperazines
dc.subjectTopotecan
dc.titleATM orchestrates the DNA-damage response to counter toxic non-homologous end-joining at broken replication forks.
dc.typeArticle
dcterms.dateAccepted2018-11-15
prism.issueIdentifier1
prism.publicationDate2019
prism.publicationNameNat Commun
prism.startingPage87
prism.volume10
pubs.funder-project-idCancer Research Uk (None)
pubs.funder-project-idCancer Research UK (18796)
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)
rioxxterms.licenseref.startdate2019-01-08
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.typeJournal Article/Review
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1038/s41467-018-07729-2

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