Thwarting endogenous stress: BRCA protects against aldehyde toxicity

Abstract

Homologous recombination (HR) and the Fanconi Anemia (FA) pathways constitute essential repair pathways for DNA damage, which includes DNA double‐stranded breaks (DSB) and inter‐strand cross‐links (ICL), respectively. Germline mutations affecting a single copy of the HR factors BRCA1 and BRCA2 predispose individuals to cancers of the breast, ovary, prostate, and pancreas. Cells deficient for BRCA proteins display high levels of genome instability due to defective repair of endogenous DSBs and are also exquisitely sensitive to DNA‐damaging agents. In addition to their roles in repair of DSBs and ICLs, HR and FA proteins have a genetically separable function in the protection of stalled DNA replication forks from nuclease‐mediated degradation (Schlacher et al, 2012). 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, 2015), 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, 2017; Tan et al, 2017).

Functions of Breast Cancer Predisposition Genes: Implications for Clinical Management

“…Dysfunction of BRCA1/2 leads to cancer susceptibility via the induction of chromosomal instability and mutagenesis [32,33]. Several studies have shown that environmental and endogenous toxins, such as aldehydes, induce genomic instability, and BRCA1 and/or BRCA2 protect against such toxicity and suppress tumorigenesis [34][35][36]. In addition, endogenous acetaldehyde toxicity may induce BRCA2 haploinsufficiency [35].…”

“…In addition, endogenous acetaldehyde toxicity may induce BRCA2 haploinsufficiency [35]. According to such reports, aldehyde accumulation may modulate tissue-specific cancer progression in BRCA1/2 GPV carriers, with implications for public health [34] • DNA Damage-induced Cell Cycle Checkpoints…”

Stem cells under the influence of alcohol: effects of ethanol consumption on stem/progenitor cells

“…This observation, originally demonstrated on murine models, was clinically corroborated by the discovery of a higher prevalence of bone-marrow failure in patients affected by Fanconi anemia harboring also a dominant negative polymorphism in the ALDH2 gene which is frequent in the Asian population [ 129 ]. Moreover, the expression BRCA1 and BRCA2 tumor suppressors genes, known to contribute to DNA repair [ 130 ], has been associated to a protective role against endogenous acetaldehyde toxicity [ 131 ]. Consequently, endogenous aldehydes may be implicated in triggering carcinogenesis in BRCA2 mutation carriers [ 132 ].…”