Study of rare human genetic diseases often leads to significant advances in the understanding of cancer biology in general. Such is the case for Fanconi Anemia (FA), a rare cancer susceptibility syndrome with an incidence of only 1 in 300,000 live births. FA is an autosomal recessive disease characterized by chromosome instability, cellular hypersensitivity to DNA cross-linking agents such as Mitomycin C (MMC) and Cisplatin, and increased predisposition to cancers, mainly leukemias and squamous cell carcinomas of the head and neck or gynecologic system (Alter et al. 2003; Bagby 2003). Although the function of the seven cloned FA genes (A, C, D1, D2, E, F, and G) is largely unknown, the genes cooperate in a common cellular pathway, known as the FA/BRCA pathway (D’Andrea and Grompe 2003). The recent identification of the breast and ovarian cancer susceptibility gene, BRCA2, as the FANCD1 gene (Howlett et al. 2002) implicates the FA/BRCA pathway in homology-directed DNA repair (HDR), and suggests that disruption of the pathway may promote breast and ovarian cancer. In the current issue of Genes and Development, Houghtaling et al.(2003) analyze mice with a targeted deletion of one of the downstream FA genes—namely, Fancd2. Their analysis defines a role for the FA pathway in HDR and (at last) provides a molecular link between the FA pathway and epithelial cancers.

Several recent studies have defined molecular interactions among the FA proteins in the pathway (Fig. 1; for review, see D’Andrea and Grompe 2003). Five of the FA proteins (A, C, E, F, and G) form a nuclear complex (Garcia-Higuera et al. 1999; Medhurst et al. 2001) required for the activation (monoubiquitination) of the downstream FANCD2 protein (Garcia-Higuera et al. 2001). This FA protein complex either has intrinsic monoubiquitin ligase activity or it regulates a monoubiquitin ligase. Following DNA damage by cross-linking agents, FANCD2 is monoubiquitinated and targeted to chromatin-associated foci, where it interacts with the breast cancer protein, BRCA1 (Garcia-Higuera et al. 2001) and the MRE11/RAD50/NBS1 (M/R/N) complex (Nakanishi et al. 2002). Moreover, the BRCA1/BARD1 heterodimeric ubiquitin ligase complex (Brzovic et al. 2001) is required for the efficient assembly of these foci (A. D’Andrea, unpubl.). Disruption of the FA/BRCA pathway results in