Interaction of the fanconi anemia proteins and BRCA1 in a common pathway

Fanconi anemia (FA) is a human autosomal recessive cancer susceptibility di sorder characterized by cellular sensitivity to mitomycin C and ionizing ra diation. Although six FA genes (for subtypes A, C, D2, E, F, and G) have be en cloned, their relationship to DNA repair remains unknown. In the current study, we show that a nuclear complex containing the FANCA, FANCC, FANCF, and FANCG proteins is required for the activation of the FANCD2 protein to a monoubiquitinated isoform. In normal (non-FA) cells, FANCD2 is monoubiqui tinated in response to DNA damage and is targeted to nuclear foci (dots). A ctivated FANCD2 protein colocalizes with the breast cancer susceptibility p rotein, BRCA1, in ionizing radiation-induced foci and in synaptonemal compl exes of meiotic chromosomes. The FANCD2 protein, therefore, provides the mi ssing link between the FA protein complex and the cellular BRCA1 repair mac hinery. Disruption of this pathway results in the cellular and clinical phe notype common to all FA subtypes.