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dc.contributor.authorTacconi, EM
dc.contributor.authorLai, X
dc.contributor.authorFolio, C
dc.contributor.authorPorru, M
dc.contributor.authorZonderland, G
dc.contributor.authorBadie, S
dc.contributor.authorMichl, J
dc.contributor.authorSechi, I
dc.contributor.authorRogier, M
dc.contributor.authorMatía García, V
dc.contributor.authorBatra, AS
dc.contributor.authorRueda, OM
dc.contributor.authorBouwman, P
dc.contributor.authorJonkers, J
dc.contributor.authorRyan, A
dc.contributor.authorReina-San-Martin, B
dc.contributor.authorHui, J
dc.contributor.authorTang, N
dc.contributor.authorBruna, A
dc.contributor.authorBiroccio, A
dc.contributor.authorTarsounas, M
dc.date.accessioned2020-08-04T15:59:30Z
dc.date.issued2017-10
dc.identifier.citationEMBO molecular medicine, 2017, 9 (10), pp. 1398 - 1414
dc.identifier.issn1757-4676
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.
dc.formatPrint
dc.format.extent1398 - 1414
dc.languageeng
dc.language.isoeng
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectCell Line, Tumor
dc.subjectFibroblasts
dc.subjectAnimals
dc.subjectHumans
dc.subjectMice
dc.subjectMice, Nude
dc.subjectFanconi Anemia
dc.subjectDNA Damage
dc.subjectAcetaldehyde
dc.subjectBRCA1 Protein
dc.subjectBRCA2 Protein
dc.subjectXenograft Model Antitumor Assays
dc.subjectRad51 Recombinase
dc.subjectFanconi Anemia Complementation Group D2 Protein
dc.subjectHomologous Recombination
dc.subjectAldehyde Dehydrogenase, Mitochondrial
dc.titleBRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity.
dc.typeJournal Article
rioxxterms.versionofrecord10.15252/emmm.201607446
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2017-10en_US
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfEMBO molecular medicine
pubs.issue10
pubs.notesNot known
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.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-statusPublished
pubs.volume9en_US
pubs.embargo.termsNot known
icr.researchteamPreclinical Modelling of Paediatric Cancer Evolutionen_US
dc.contributor.icrauthorBruna Cabot, Alejandraen


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