Chromatin State Alterations in Fanconi Anemia Hematologic Disease and Bone Marrow Failure

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PROJECT SUMMARY/ABSTRACT Fanconi anemia (FA) is a genetic disease characterized by congenital abnormalities, hematologic disease and bone marrow failure, increased cancer risk, and premature mortality. Therapeutic options for FA are extremely limited and the overall life expectancy of FA patients is only 29 years. The molecular etiology of FA is poorly understood and no rational therapeutic approaches based on the biochemistry of this disease have been developed. Consequently, the prognosis for FA patients - and their families and loved ones - is poor. Progress in this field will only be achieved by a greater understanding of the molecular basis of this disease, underscoring the significance of our proposed studies. FA is caused by mutations in any one of 23 genes. The FA proteins function to repair DNA damage and to maintain chromosome stability. A key step in the activation of the FA pathway is the monoubiquitination of the FANCD2 and FANCI proteins, which occurs upon exposure to DNA damaging agents. The monoubiquitination of FANCD2 and FANCI promotes their assembly into discrete chromatin-associated foci. The mechanisms by which FANCD2 and FANCI are targeted to, retained in, and function within chromatin are, however, largely unknown. Importantly, FANCD2 and FANCI monoubiquitination is defective in >90% of FA patients and integral to FA patient BMF and hematologic disease. The overarching goal of our 3-year SHINE II R01 research proposal (parent award) is to elucidate the molecular underpinnings of the connections between FA and chromatin plasticity. Directly related to this goal, we propose that FANCD2 regulates the expression of select large transcriptionally active units under conditions of replication stress. We further speculate that the cohort of FANCD2-regulated large genes will be cell-type specific. The major goals of this Graduate Student Diversity Supplement are to directly test these hypotheses. Our studies have the potential to open a new avenue of therapeutic intervention for FA.