Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice

Individuals with Fanconi anaemia exhibit developmental defects, stem-cell failure and a strong predisposition to leukaemia. Cells derived from patients with Fanconi anaemia are susceptible to DNA damage caused by DNA crosslinking agents such as cisplatin and mitomycin C. These are cancer chemotherapeutics, so cells are not normally exposed to them, prompting the question: what is the natural source of DNA damage repaired by this pathway? Experiments with mice deficient in Fancd2 (one of several Fanconi anaemia genes) and Aldh2 (which encodes an enzyme that detoxifies aldehydes) suggest that acetaldehyde is an endogenous source of DNA damage in Fanconi anaemia, contributing to cancer predisposition and haematopoeitic failure. Intriguingly, these mouse models also suggest a possible mechanism for the damaging effects of fetal alcohol exposure during pregnancy.