The Comprehensive Center for Fanconi Anemia & The Cytogenetic Facility

The Comprehensive Center for Fanconi Anemia & The Cytogenetic Facility

Our laboratory is interested in the molecular events involved in normal blood cell formation and in the molecular cause of leukemia and other cancers. A major focus of the lab is the normal, physiologic activation of the cell surface receptor for erythropoietin. We are interested in the early signal transduction events that follow cytokine activation, such as activation of JAK kinases and STAT transcription factors, and in the later events, such as the induction of cytokine-specific genes. Recently, we have identified and cloned a family of cytokine-inducible deubiquitinating enzymes that regulate hematopoietic cell growth. These enzymes regulate growth by controlling the ubiquitin-mediated proteolysis of intracellular growth regulatory proteins.

More recently, our laboratory has become interested in the molecular cause of Fanconi Anemia (FA). FA is a human autosomal recessive disease characterized by spontaneous chromosome breakage, bone marrow failure, and cancer susceptibility. Cells from FA patients are hypersensitive to ionizing radiation (IR) and to the DNA crosslinking agent, mitomycin C (MMC), and these cells have a defect in DNA repair. cDNAs corresponding to six of the eight Fanconi Anemia complementation groups have been isolated. Although the precise cellular function of the encoded FA polypeptides remains unknown, we have determined that five of the FA proteins (A,C,E,F,G) are subunits of a large nuclear protein complex. Mutations in any one of these five proteins results in disruption of the protein complex, leading to the characteristic cellular and clinical features of FA. Interestingly, the sixth cloned FA protein, FANCD, functions as a substrate downstream of the FA protein complex. The FANCD protein plays a more direct role in the regulation of DNA repair. The major focus of our laboratory is the elucidation of the proteins interacting with the FA pathway, such as BRCA1 and ATM, and the cellular role of this pathway in maintaining chromosome stability. While FA is itself a rare disease, mutations (acquired loss of function) of Fanconi related genes may play a common role in the pathogenesis of many cancers in the general (non-FA) population.

References:
D'Andrea, A.D. 1996. Fanconi Anemia Forges a Novel Pathway. Nature Genetics 1996;14: 240-242.

Garcia-Higuera I, Taniguchi T, Ganesan S, Meyn MS, Timmers C. Hejna J, Grompe M, D'Andrea AD. Interaction of the Fanconi Anemia Proteins and BRCA1 in a Common Pathway. Molecular Cell 7:249-262, 2001.

Taniguchi T, Garcia-Higuera I, Xu B, Andreassen P, Gregory RC, Lane WS, Kim S-T, Kastan MB, D'Andrea AD. Convergence of the Fanconi Anemia and Ataxia Telangiectasia Signaling Pathways. Cell 109:459-472, 2002.