The long term goals of this project are to elucidate both the 'logic' and molecules involved in the genomic stability of hematopoietic cells through studies of Fanconi anemia (FA). Three FA genes have now been cloned, and the investigator is poised to ask precise questions about the organization and function of their protein products. Although the cellular phenotype of FA implicates these proteins in drug-sensitive pathways as """"""""gatekeepers"""""""" of genomic stability, their molecular functions remain incompletely understood. FANCC has a role in cellular detoxification by virtue of its interaction with NADPH cytochrome P-450 reductase (RED) and regulation of a pre-DNA damage step. FANCA is homologous to peroxidases, interacts with FANCG, and functions in the nucleus. Using cell culture yeast and mouse models, the investigator proposes to test the hypothesis that cytoplasmic FANCC-RED and nuclear FANCA-FANCG complexes perform detoxification functions in their respective cellular compartments. Thus, the investigator will (I) characterize the expression patterns of FA gene products during mouse embryogenesis, including hematopoietic and germ cell development, by in situ and biochemical strategies; (II) determine the oligomeric structure and regulation of FA proteins; (III) use genetic strategies to IocaIize the function of FA proteins to pre- or post-DNA damage steps, and, in this context, test the function of the FANCA peroxidase domain; and (IV) isolate genes that regulate the FANCC-RED pathway, and characterize the relationship of this pathway to that regulated by FANCA-FANCG. Our combined genetic, cellular and biochemical approaches should result in a comprehensive view of the regulation and function of FA gene products. Aside from improving our understanding of fundamental mechanisms of cellular detoxification and chromosomal stability relevant to hematopoiesis, the manipulation of drug-sensitive pathways controlled by FA genes will provide novel translational opportunities for chemosensitization of leukemias or solid tumors to bifunctional cross-linkers.
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