Molecular Pathogenesis of Fanconi Anemia

Dana-Farber Cancer Inst, Boston MA

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Abstract

? DESCRIPTION (provided by applicant): Fanconi Anemia (FA) is a rare inherited autosomal recessive genomic instability disorder characterized by developmental abnormalities, bone marrow failure (BMF), myelodysplastic syndrome (MDS), acute myeloblastic leukemia (AML) susceptibility, and hypersensitivity to DNA crosslinking agents. The study of this rare disease is significant because it has led to a broader understanding of BMF, MDS, and AML in the general (non-FA) population. FA patients often present with MDS or AML, with the highest frequency during their teens or young adulthood. It is estimated that 19% of FA patients present with MDS, usually exhibiting refractory cytopenia and multilineage dysplasia. There are sixteen known FA genetic subtypes, and the encoded FA proteins cooperate in a common DNA repair pathway, the so-called Fanconi Anemia/BRCA pathway (D'Andrea AD. Susceptibility pathways in Fanconi's anemia and breast cancer: 2010 N Engl J Med 362: 1909-1919). Inherited or acquired disruption of this pathway leads to the characteristic chromosome instability phenotype of FA. In the FA/BRCA pathway, DNA damage activates the assembly of at least eight of the FA proteins into a Fanconi Anemia (FA) core complex which translocates to the site of the damage. The FA core complex, in turn, monoubiquitinates the FANCD2/FANCI heterodimer at this site. Monoubiquitinated FANCD2 subsequently binds FANCP/SLX4 (an endonuclease complex), via the monoubiquitin binding pocket (UBZ4 domain) of FANCP/SLX4. FANCP/SLX4 in turn mediates the excision of the DNA crosslink. The resulting double strand break is repaired by the downstream FA proteins (D1/BRCA2, O, N). After completion of DNA repair, the FANCD2-Ub protein is deubiquitinated by USP1. The purpose of this new application is to examine novel regulatory features of the FA/BRCA pathway. During the five-year study period we plan 1) to determine the functional role of sumoylation of the Fanconi Anemia core complex in the FA/BRCA pathway, 2) to determine the functional role of new subunits of the Fanconi Anemia core complex in the FA/BRCA pathway, and 3) to determine the different roles of FANCD2 and FANCI in the FA/BRCA pathway.