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).
Highlights
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
Mutations in ALDH2, the enzyme required for acetaldehyde metabolism, are associated with predisposition to cancer signifying its critical role in the removal of genotoxic metabolic intermediates (Cai et al, 2015)
How does a DNA-damaging agent like acetaldehyde lead to the inhibition of tumor growth? Assuming that acetaldehyde induces cross-links, DSB intermediates might be expected to form after the replication fork collides with the lesion, which would require error-free repair by HR
Summary
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. Tacconi et al (2017) 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 1): (i) While HR functions are restored, BRCA1 and 53BP1 double-deficient cells are not protected from replication fork degradation (Ray Chaudhuri et al, 2016), and acetaldehyde treatment induces replication stress in these cells (Tacconi et al, 2017); (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, 2012); (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, 2017).
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