BRCA1 and BRCA2 tumor suppressors protect against endogenous acetaldehyde toxicity.
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Date
2017-10-01ICR Author
Author
Tacconi, EM
Lai, X
Folio, C
Porru, M
Zonderland, G
Badie, S
Michl, J
Sechi, I
Rogier, M
Matía García, V
Batra, AS
Rueda, OM
Bouwman, P
Jonkers, J
Ryan, A
Reina-San-Martin, B
Hui, J
Tang, N
Bruna, A
Biroccio, A
Tarsounas, M
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Cell Line, Tumor
Fibroblasts
Animals
Humans
Mice
Mice, Nude
Fanconi Anemia
DNA Damage
Acetaldehyde
BRCA1 Protein
BRCA2 Protein
Xenograft Model Antitumor Assays
Rad51 Recombinase
Fanconi Anemia Complementation Group D2 Protein
Homologous Recombination
Aldehyde Dehydrogenase, Mitochondrial
Research team
Preclinical Modelling of Paediatric Cancer Evolution
Language
eng
License start date
2017-10
Citation
EMBO molecular medicine, 2017, 9 (10), pp. 1398 - 1414
Publisher
WILEY