Differential regulation of retinoic acid metabolism in Fanconi anemia

Fanconi anemia (FA) is a genetic disease characterized by congenital abnormalities and increased risk for bone marrow failure and cancer. FA is caused by mutation of 23 genes, the protein products of which function in the maintenance of genome stability. An important role for the FA proteins in the repair of DNA interstrand crosslinks (ICLs) has been established. While the endogenous sources of ICLs relevant to the pathophysiology of FA have yet to be determined, a role for the FA proteins in the detoxification of reactive metabolic aldehydes has been established. To discover new metabolic pathways linked to FA, we performed RNA-seq analysis on a previously established isogenic FA-D2 patient cell model. Multiple retinoic acid metabolism and signaling genes were differentially expressed in the FA-D2 patient cells, including ALDH1A1 and RDH10, two key enzymes in the retinoic acid pathway. Increased levels of ALDH1A1 and RDH10 were confirmed by immunoblotting. FA-D2 (FANCD2^-/-) patient cells displayed increased aldehyde dehydrogenase activity compared to the FANCD2-complemented cells. Following exposure to retinaldehyde, FA-D2 (FANCD2^-/-) patient cells exhibited increased DNA damage and checkpoint activation. Our findings provide an example of a novel link between retinoic acid metabolism and FA and suggest that retinaldehyde may be an additional reactive metabolic aldehyde relevant to the pathophysiology of FA.