Abstract
Inherited BRCA2 mutations promote genome instability via aldehyde-induced BRCA2 degradation.
Major finding: Inherited BRCA2 mutations promote genome instability via aldehyde-induced BRCA2 degradation.
Mechanism: Aldehyde-generated BRCA2 haploinsufficiency causes MRE11-driven RNA–DNA hybrid formation.
Impact: Compounds that are both endogenous and environmental may promote cancer in BRCA2 mutation carriers.
Inheritance of a single mutant copy of BRCA2 predisposes to cancer. Some inherited BRCA2 missense mutations can mislocalize wild-type (WT) BRCA2 protein to cause genomic instability. But how inherited BRCA2 truncating mutations, which are the most prevalent type of BRCA2 mutations, cause cancer susceptibility is less clear. In this report, Tan and colleagues describe a mechanism by which formaldehyde, which is both a cellular metabolite and an environmental toxin, triggers genomic instability in cells harboring BRCA2 truncating mutations. These abnormalities occur because formaldehyde triggers DNA replication fork stalling accompanied by the selective degradation of BRCA2 protein. In cells heterozygous for truncating BRCA2 mutations—where preexisting WT BRCA2 protein levels are already low—naturally occurring concentrations of formaldehyde induced BRCA2 haploinsufficiency, leading to increased MRE11-mediated degradation of nascent DNA strands, which is normally blocked by the presence of BRCA2 at stalled replication forks. Similar effects occurred in parental cells with WT BRCA2 after prolonged formaldehyde exposure, but BRCA2 heterozygous cells were more sensitive than WT cells. Further, formaldehyde treatment increased the frequency of structural chromosomal aberrations, particularly aberrations typical of BRCA2 deficiency, in BRCA2 heterozygous cells. Consistent with these findings, treatment with an MRE11 inhibitor or expression of full-length BRCA2 prevented formaldehyde-mediated DNA damage and chromosomal aberrations in BRCA2 heterozygous cells. Dissolution of RNA–DNA hybrids using RNAse H1 decreased formaldehyde-induced DNA replication stalling and the frequency of structural chromosomal aberrations in both parental and BRCA2 heterozygous cells, suggesting that formaldehyde induces DNA replication stress via the formation of RNA–DNA hybrids in BRCA2 heterozygous cells. Similarly, acetaldehyde, which is an ethanol catabolite, also induces DNA replication stress in BRCA2 heterozygous cells at concentrations that do not affect parental cells. Together, these results suggest that environmental or endogenous aldehydes may drive cancer susceptibility in individuals who inherit heterozygous BRCA2 truncating mutations, with potential implications for public health in mutation carriers.
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