These results outline the mechanisms by which the mouse haematopoietic system and, more specifically, blood stem cells respond to an endogenous and alcohol-derived source of DNA damage. Primary protection against acetaldehyde is provided by Aldh2-mediated detoxification and, when this is lost or saturated, acetaldehyde damages DNA. The Fanconi anaemia pathway is the principal mechanism to counteract this damage, but NHEJ and homologous recombination can also deal with these lesions. These results therefore illustrate that coordinated pathway choice is critical for maintaining genome stability upon aldehyde exposure. The Fanconi anaemia pathway prevents aldehyde lesions from degenerating into double-stranded breaks, the illegitimate repair of which leads to a characteristic pattern of mutagenesis in HSCs (Extended Data Fig. 11). Aldehydes are capable of forming a diverse range of DNA lesions—from base adducts to DNA–DNA or DNA–protein crosslinks. The known molecular function of the Fanconi anaemia pathway suggests that the most physiologically toxic lesion caused by aldehydes may be a DNA interstrand crosslink. However, if it is indeed an interstrand crosslink, then the factors involved in translesion synthesis or homologous recombination processes are distinct
