Study of molecular pathogenesis of Fanconi anemia

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Fanconi anemia is an autosomal recessive disorder of hematopoiesis with at least 11 genetically different groups, characterized by cellular hypersensitivity to DNA cross-linkers and chromosome instability. To date, 8 genes have been identified. A multiprotein complex including these gene products, FANCAICJE/F/G/L is required for activation of FANCD2 into a monoubiquitinated form. This active form affects genomic instability in collaboration with BRCA1 and BRCA2IFANCD1. In this project, we studied functions of FANCA mutants with amino acid substitution in its N-terminal region including nuclear localization signal and FANCG-binding sites. Our results indicate that formation of a stable complex including FANCAICIE/FIGIL is not essential for FANCD2 activation. It seems that nuclear import of FANCA/L complex palys a central role in this pathway, and that FANCG negatively regulates nuclear import of FANCA. Furthermore, we identified Hsc7O as a FANCA-binding protein. A dominant-negative form of Hsc7O and 17-AAG, a specific inhibitor of Hsp9O, inhibited nuclear localization of FANCA, suggesting that a chaperone complex including Hsc7O is required for nuclear import of FANCA. We identified FANCA mutations in 27 Japanese FA patients and found novel molecular mechanisms of generation of large deletions in this gene. We found that long-term remission of bone marrow failurewas associated with myeloid lineage-selective expansion of cells with reversion in a patient. This case suggests the clinical usefulness of gene therapy.