July 2008

Document Type


Degree Name



Dept. of Biochemistry and Molecular Biology


Oregon Health & Science University


Fanconi anemia (FA) is a recessive inherited disease characterized by bone marrow failure, congenital abnormalities, and a predisposition to cancer. Since 1992 when the first FA gene (FANCC) was cloned, a total of 13 genes have been identified. Because hypersensitivity to cross-linking agents is a consistent feature of this disorder, most research in the field has been and continues to be focused on the role of the FA gene products in maintaining chromosomal stability. In contrast, the molecular pathogenesis of marrow failure in this disorder, the leading cause of death, has not been clarified. The focus of my thesis work has been to define the potential roles of these gene products in supporting the replication and survival of hematopoietic cells. Several pathophysiological mechanisms have been defined by our laboratory. First, FA hematopoietic cells are hypersensitive to tumor necrosis factor (TNF)-α induced apoptosis. Second, for reasons as yet unexplained, TNF-α production is increased in hematopoietic cells from FA patients and Fancc-/- knockout mice. The first project of this thesis addressed this problem using systems biology approaches followed by biochemical studies. This project describes the discovery that FANCC modulates the activation potential and activation state of toll-like receptor (TLR) 8 and that the overproduction of TNF-α by FA-C cells devolves from the unmodulated state of this particular TLR molecule. The second project has established a key survival signaling function for FANCC, FANCG and FANCD2. Specifically, we identified STAT5 activation defects in cells with inactivating mutations of FANCC, FANCG and FANCD2. Based upon the biochemical studies we have completed, we report that activation of the STAT5 signaling pathway requires inducible intermolecular interactions involving STAT5, FANCC and FANCD2 and that these interactions require FANCG. Moreover, we provide evidence that these proteins influence specifically the nuclear translocation of tyrosine phosphorylated STAT5. Because STAT5 is a key signaling molecule for survival and replication of hematopoietic stem and progenitor cells, we argue that failure of the STAT5 signaling pathway is partly responsible for the hematopoietic phenotype of FA. Because both of the functions I define for these gene products are not dependent upon the nuclear “core complex” (which participates in the responses of normal cells to cross-linking agents), our work confirms that at least three FA genes are multifunctional. We anticipate that the other ten FA genes will also be shown to encode proteins that function in survival signaling pathways of relevance to hematopoietic cells.




School of Medicine



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