STRUCTURAL ANALYSIS OF FANCONI ANEMIA PROTEINS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Fanconi anemia (FA) is a rare genetic disease characterized by birth defects, progressive bone marrow failure and predisposition to cancer, such as acute myeloid leukemia (AML) and squamous cell carcinomas. At the cellular level, FA is characterized by chromosomal instability and hypersensitivity to agents that cause DNA interstrand crosslinks (ICL), such as mitomycin C and diepoxybutane.On the basis of somatic cell fusion studies, FA has been divided into at least 11 complementation groups (A,B,C,D1,D2,E,F,G, I, J, and L). Until recently, ten of which have been cloned. We have determined the crystal structures of three FA protein fragments,namely the N-terminal portion of FA-D2, C-terminal fragments of FA-E and FA-F. Interestingly, all of these structures consist of common helical repeats, which are predicted to be present in other fanconi anemia proteins as well. We've obtained crystals of a FancA/FancG protein complex that are amenable to X-ray diffraction. We are in the process of determining its structure, which will certainly help us to understand more of the FA pathway.