BRCA 1 and BRCA 2 tumor suppressors protect against endogenous acetaldehyde toxicity

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 FANCD 2. Here, we investigate whether HR ‐compromised cells are sensitive to acetaldehyde, similarly to FANCD 2‐deficient cells. We demonstrate that inactivation of HR factors BRCA 1, BRCA 2, or RAD 51 hypersensitizes cells to acetaldehyde treatment, in spite of the FA pathway being functional. Aldehyde dehydrogenases ( ALDH s) play key roles in endogenous acetaldehyde detoxification, and their chemical inhibition leads to cellular acetaldehyde accumulation. We find that disulfiram (Antabuse), an ALDH 2 inhibitor in widespread clinical use for the treatment of alcoholism, selectively eliminates BRCA 1/2‐deficient cells. Consistently, Aldh2 gene inactivation suppresses proliferation of HR ‐deficient mouse embryonic fibroblasts ( MEF s) and human fibroblasts. Hypersensitivity of cells lacking BRCA 2 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 BRCA 2 and FANCD 2 for protection against MRE 11‐dependent degradation. Importantly, acetaldehyde specifically inhibits in vivo the growth of BRCA 1/2‐deficient tumors and ex vivo in patient‐derived tumor xenograft cells ( PDTC s), 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 BRCA 1/2‐deficient cells and tumors.