Epithelial cancer in Fanconi anemia complementation group D2 (Fancd2) knockout mice

Abstract

Fanconi anemia (FA) is a genetic disorder characterized by hypersensitivity to DNA damage, bone marrow failure, congenital defects, and cancer. To further investigate the in vivo function of the FA pathway, mice with a targeted deletion in the distally acting FA geneFancd2were created. Similar to human FA patients and other FA mouse models,Fancd2mutant mice exhibited cellular sensitivity to DNA interstrand cross-links and germ cell loss. In addition, chromosome mispairing was seen in male meiosis. However,Fancd2mutant mice also displayed phenotypes not observed in other mice with disruptions of proximal FA genes. These include microphthalmia, perinatal lethality, and epithelial cancers, similar to mice withBrca2/Fancd1hypomorphic mutations. These additional phenotypes were not caused by defects in the ATM-mediated S-phase checkpoint, which was intact in primaryFancd2mutant fibroblasts. The phenotypic overlap betweenFancd2-null andBrca2/Fancd1hypomorphic mice is consistent with a common function for both proteins in the same pathway, regulating genomic stability.