Our genome is constantly damaged by agents from within or outside our cells causing DNA lesions. Failure to repair these lesions by any of the numerous cellular DNA repair pathways can lead to genome instability and the development of genetic diseases such as cancer. A particularly hazardous type of DNA damage is an interstrand crosslink (ICL) that can be induced by widely used cancer chemotherapeutics but also by endogenous metabolites. It was long thought that there was only one pathway that could repair these lesions, the Fanconi anemia pathway, a DNA repair pathway affected in the cancer predisposition syndrome Fanconi anemia (FA). The FA pathway is a complex multi-subunit DNA repair pathway of which many mechanistic details are still missing. Recently, we discovered an additional ICL repair pathway which repairs endogenous ICLs induced by acetaldehyde, a product of alcohol metabolism. However, the molecular mechanism of this pathway is mostly unknown. In this project we will investigate the missing details of the Fanconi anemia ICL repair pathway and define the mechanism(s) of repair of aldehyde induced ICLs. These studies will provide important novel insights into how cells maintain genome integrity, increase our understanding of Fanconi anemia, and could provide new clues to improve strategies in chemotherapeutic treatment.