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dc.contributor.authorTacconi, EMen_US
dc.contributor.authorLai, Xen_US
dc.contributor.authorFolio, Cen_US
dc.contributor.authorPorru, Men_US
dc.contributor.authorZonderland, Gen_US
dc.contributor.authorBadie, Sen_US
dc.contributor.authorMichl, Jen_US
dc.contributor.authorSechi, Ien_US
dc.contributor.authorRogier, Men_US
dc.contributor.authorMatía García, Ven_US
dc.contributor.authorBatra, ASen_US
dc.contributor.authorRueda, OMen_US
dc.contributor.authorBouwman, Pen_US
dc.contributor.authorJonkers, Jen_US
dc.contributor.authorRyan, Aen_US
dc.contributor.authorReina-San-Martin, Ben_US
dc.contributor.authorHui, Jen_US
dc.contributor.authorTang, Nen_US
dc.contributor.authorBruna, Aen_US
dc.contributor.authorBiroccio, Aen_US
dc.contributor.authorTarsounas, Men_US
dc.date.accessioned2020-08-04T15:59:30Z
dc.date.issued2017-10en_US
dc.identifier.citationEMBO molecular medicine, 2017, 9 (10), pp. 1398 - 1414en_US
dc.identifier.issn1757-4676en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3898
dc.identifier.eissn1757-4684en_US
dc.identifier.doi10.15252/emmm.201607446en_US
dc.description.abstractMaintenance of genome integrity requires the functional interplay between Fanconi anemia (FA) and homologous recombination (HR) repair pathways. Endogenous acetaldehyde, a product of cellular metabolism, is a potent source of DNA damage, particularly toxic to cells and mice lacking the FA protein FANCD2. Here, we investigate whether HR-compromised cells are sensitive to acetaldehyde, similarly to FANCD2-deficient cells. We demonstrate that inactivation of HR factors BRCA1, BRCA2, or RAD51 hypersensitizes cells to acetaldehyde treatment, in spite of the FA pathway being functional. Aldehyde dehydrogenases (ALDHs) play key roles in endogenous acetaldehyde detoxification, and their chemical inhibition leads to cellular acetaldehyde accumulation. We find that disulfiram (Antabuse), an ALDH2 inhibitor in widespread clinical use for the treatment of alcoholism, selectively eliminates BRCA1/2-deficient cells. Consistently, <i>Aldh2</i> gene inactivation suppresses proliferation of HR-deficient mouse embryonic fibroblasts (MEFs) and human fibroblasts. Hypersensitivity of cells lacking BRCA2 to acetaldehyde stems from accumulation of toxic replication-associated DNA damage, leading to checkpoint activation, G2/M arrest, and cell death. Acetaldehyde-arrested replication forks require BRCA2 and FANCD2 for protection against MRE11-dependent degradation. Importantly, acetaldehyde specifically inhibits <i>in vivo</i> the growth of BRCA1/2-deficient tumors and <i>ex vivo</i> in patient-derived tumor xenograft cells (PDTCs), including those that are resistant to poly (ADP-ribose) polymerase (PARP) inhibitors. The work presented here therefore identifies acetaldehyde metabolism as a potential therapeutic target for the selective elimination of BRCA1/2-deficient cells and tumors.en_US
dc.formatPrinten_US
dc.format.extent1398 - 1414en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectCell Line, Tumoren_US
dc.subjectFibroblastsen_US
dc.subjectAnimalsen_US
dc.subjectHumansen_US
dc.subjectMiceen_US
dc.subjectMice, Nudeen_US
dc.subjectFanconi Anemiaen_US
dc.subjectDNA Damageen_US
dc.subjectAcetaldehydeen_US
dc.subjectBRCA1 Proteinen_US
dc.subjectBRCA2 Proteinen_US
dc.subjectXenograft Model Antitumor Assaysen_US
dc.subjectRad51 Recombinaseen_US
dc.subjectFanconi Anemia Complementation Group D2 Proteinen_US
dc.subjectHomologous Recombinationen_US
dc.subjectAldehyde Dehydrogenase, Mitochondrialen_US
dc.titleBRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity.en_US
dc.typeJournal Article
rioxxterms.versionofrecord10.15252/emmm.201607446en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2017-10en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfEMBO molecular medicineen_US
pubs.issue10en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Preclinical Modelling of Paediatric Cancer Evolution
pubs.publication-statusPublisheden_US
pubs.volume9en_US
pubs.embargo.termsNot knownen_US
icr.researchteamPreclinical Modelling of Paediatric Cancer Evolutionen_US
dc.contributor.icrauthorBruna Cabot, Alejandraen_US


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