dc.contributor.author | Tacconi, EM | |
dc.contributor.author | Lai, X | |
dc.contributor.author | Folio, C | |
dc.contributor.author | Porru, M | |
dc.contributor.author | Zonderland, G | |
dc.contributor.author | Badie, S | |
dc.contributor.author | Michl, J | |
dc.contributor.author | Sechi, I | |
dc.contributor.author | Rogier, M | |
dc.contributor.author | Matía García, V | |
dc.contributor.author | Batra, AS | |
dc.contributor.author | Rueda, OM | |
dc.contributor.author | Bouwman, P | |
dc.contributor.author | Jonkers, J | |
dc.contributor.author | Ryan, A | |
dc.contributor.author | Reina-San-Martin, B | |
dc.contributor.author | Hui, J | |
dc.contributor.author | Tang, N | |
dc.contributor.author | Bruna, A | |
dc.contributor.author | Biroccio, A | |
dc.contributor.author | Tarsounas, M | |
dc.date.accessioned | 2020-08-04T15:59:30Z | |
dc.date.issued | 2017-10-01 | |
dc.identifier.citation | EMBO molecular medicine, 2017, 9 (10), pp. 1398 - 1414 | |
dc.identifier.issn | 1757-4676 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3898 | |
dc.identifier.eissn | 1757-4684 | |
dc.identifier.doi | 10.15252/emmm.201607446 | |
dc.description.abstract | Maintenance 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, Aldh2 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 in vivo the growth of BRCA1/2-deficient tumors and ex vivo 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.format | Print | |
dc.format.extent | 1398 - 1414 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | WILEY | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Fibroblasts | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Mice, Nude | |
dc.subject | Fanconi Anemia | |
dc.subject | DNA Damage | |
dc.subject | Acetaldehyde | |
dc.subject | BRCA1 Protein | |
dc.subject | BRCA2 Protein | |
dc.subject | Xenograft Model Antitumor Assays | |
dc.subject | Rad51 Recombinase | |
dc.subject | Fanconi Anemia Complementation Group D2 Protein | |
dc.subject | Homologous Recombination | |
dc.subject | Aldehyde Dehydrogenase, Mitochondrial | |
dc.title | BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity. | |
dc.type | Journal Article | |
rioxxterms.versionofrecord | 10.15252/emmm.201607446 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2017-10 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | EMBO molecular medicine | |
pubs.issue | 10 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 9 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Preclinical Modelling of Paediatric Cancer Evolution | |
dc.contributor.icrauthor | Bruna Cabot, Alejandra | |