A physical complex of the Fanconi anemia proteins FANCG/XRCC9 and FANCA

Fanconi anemia (FA) is a recessively inherited disease characterized at the cellular level by spontaneous chromosomal instability and specific hyperse nsitivity to cross-linking agents. FA is genetically heterogeneous, compris ing at least eight complementation groups (A-H). We report that the protein encoded by the gene mutated in complementation group G (FANCG) localizes t o the cytoplasm and nucleus of the cell and assembles in a molecular comple x with the FANCA protein, both in vivo and in vitro. Endogenous FANCA/FANCG complex was detected in both non-FA cells and in FA cells from groups D an d E. By contrast, no complex was detected in specific cell lines belonging to groups A and G, whereas reduced levels were found in cells from groups B , C, F, and H, Wild-type levels of FANCA/ FANCG complex were restored upon correction of the cellular phenotype by transfection or cell fusion experim ents, suggesting that this complex is of functional significance in the FA pathway. These results indicate that the cellular FA phenotype can be conne cted to three biochemical subtypes based on the levels of FANCA/FANCG compl ex. Disruption of the complex may provide an experimental strategy for chem osensitization of neoplastic cells.