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

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.

Chlorambucil targets BRCA 1/2‐deficient tumours and counteracts PARP inhibitor resistance

“…Moreover, we tested chlorambucil in cellular models in which BRCA1 gene inactivation is associated with olaparib resistance. Olaparib sensitivity characteristic of Brca1 ‐deleted mouse mammary tumour‐derived cells is abrogated upon loss of 53BP1 (Fig B; Bouwman et al , ; Tacconi et al , ). Nevertheless, these cells remained hypersensitive to cisplatin and chlorambucil.…”

Homology-Directed Repair and the Role of BRCA1, BRCA2, and Related Proteins in Genome Integrity and Cancer

“…Although the role of BRCA1 / 2 in counteracting the toxic effects of aldehydes has not been studied in the same capacity using mouse models, it has been investigated extensively in human cancer cell lines and mouse embryonic fibroblasts (MEFs) (Tacconi et al 2017). BRCA1/2-deficient human cancer cells are sensitive to treatment with acetaldehyde or disulfiram, an inhibitor of ALDH2, and Aldh2 -null MEFs show synthetic lethality with BRCA1/2 deficiency.…”

Thwarting endogenous stress: BRCA protects against aldehyde toxicity

“…New work from Madalena Tarsounas shows that inactivation of HR factors BRCA1, BRCA2, and RAD51 in cell lines results in hypersensitization to either genetic ablation or chemical inhibition of the acetaldehyde metabolizing enzyme ALDH2 (Tacconi et al , ). Moreover, treatment with acetaldehyde in BRCA1‐ and BRCA2‐deficient mouse tumor models and patient‐derived tumor xenografts in vivo results in regression of tumors.…”

“…However, Tacconi et al () find that BRCA1/53BP1‐deficient tumors, which are HR proficient, are exquisitely sensitive to acetaldehyde treatments in vivo . This surprising observation might be explained by three non‐mutually exclusive mechanisms (Fig ): (i) While HR functions are restored, BRCA1 and 53BP1 double‐deficient cells are not protected from replication fork degradation (Ray Chaudhuri et al , ), and acetaldehyde treatment induces replication stress in these cells (Tacconi et al , ); (ii) BRCA1 has a role in cross‐link repair upstream of its role in HR, and BRCA1/53BP1‐deficient cells remain hypersensitive to DNA cross‐links (Bunting et al , ); (iii) a recent report from the laboratory of Ashok Venkitaraman has shown that exposure to aldehydes causes selective degradation of BRCA2 resulting in “induced haploinsufficiency” for BRCA2 (see below) (Tan et al , ). The reduction in the levels of BRCA2 upon acetaldehyde treatments could result in HR defects that re‐sensitize BRCA1/53BP1‐deficient tumors, which were initially proficient for HR.…”

“…Although it has been hypothesized that loss of functional HR and ICL repair is the primary cause of cancer in BRCA ‐ and FA ‐deficient patients (Prakash et al , ), the contribution of replication fork instability associated with the degradation of nascent DNA remains unclear. Two recent papers explain how endogenous toxins render cells vulnerable to genomic instability, which explains how the BRCA / FA pathway suppresses tumorigenesis (Tacconi et al , ; Tan et al , ).…”