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 22 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. Our preliminary data, and recently published studies from our group and others, have shaped the novel hypothesis to be tested in this proposal: We hypothesize that the FANCD2 protein is a bivalent nucleosome reader, binding to methylated histones via a newly-discovered methyl-binding domain and binding to ubiquitinated histones via its CUE ubiquitin-binding domain. Nucleosome binding promotes localized chromatin remodeling at sites of DNA damage to facilitate the recruitment of downstream DNA repair proteins. Consequently, loss or mutation of FANCD2 will be manifested as global alterations of chromatin state, defective DNA repair, and chromosome instability. In summary, the overarching goal of our 3-year SHINE II R01 research proposal is to elucidate the molecular underpinnings of the connections between FA and chromatin plasticity. We anticipate that elucidation of the mechanistic links between the FA pathway and chromatin plasticity has the potential to open up a new avenue of epigenetics-based therapeutic exploration and opportunity for FA.