| Research Abstract |
Fanconi Anemia (FA) is an autosomal recessive cancer susceptibility syndrome with at least eight complementation groups (A-H). Two FA genes, corresponding to complementation groups A and C, have been cloned, but the function of the FAA and FAC proteins remains unknown. It has recently been shown that the FAA and FAC proteins bind and form a nuclear complex. In the current study, we analyzed FAA and FAC proteins in normal lymphoblasts and in lymphoblasts derived from several FA patients, including patients from group A (5 patients), B (2 patients), C (1 patient), D (4 patients), E (3 patients), F (1 patient), G (2 patients), and H (1 patient). In normal lymphoblasts, the FAA protein was phosphorylated, and its phosphorylation correlated with FAA/FAC binding and FAA/FAC nuclear accumulation. By phosphoamino acid anaylsis, FAA was phosphorylated primarily on serine residues. In contrast, in all FA cell lines derived from groups A, B, C, E, F, G, and H, phosphorylation of FAA was not observed, and FAA/FAC binding and FAA/FAG nuclear accumulation were defective. Interestingly, FA-D cells were distinct from other FA complementation groups. All four FA-D cell lines remained sensitive to Mitomycin C, despite FAA phosphorylation, FAA/FAC binding, and normal nuclear accumulation of the protein complex. Taken together, these results suggestthat the proteins encoded by the FAB, FAE, FAF, FAG, and FAH genes regulate the phosphorylation, binding, and nuclear transport of the FAA/FAC protein complex. In contrast, the protein encoded by the FAD gene may function independently or downstream of the FAA/FAC complex. These serial events in the FA pathway are required for the maintenance of genomic stability and normal hematopoiesis.
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