3 years ago

Thwarting endogenous stress: BRCA protects against aldehyde toxicity

Thwarting endogenous stress: BRCA protects against aldehyde toxicity
André Nussenzweig, Arnab Ray Chaudhuri
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, ). 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, ). Ray Chaudhuri and André Nussenzweig discuss the findings by Tacconi, Tarsounas et al in this issue of EMBO Molecular Medicine and by Tan, Venkitaraman et al in Cell on the protective role of BRCA against aldehyde toxicity.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.15252/emmm.201708194

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