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Fanconi anemia is a genetic disease characterized by bone marrow failure, congenital defects of the skin and other organs, and increased risk of malignancies. The gene for FA has been cloned, and a “bait” fragment of FA DNA has been used in several genetic screens in yeast to identify new genes involved in cellular proliferation and in DNA repair. One of these genes, designated MMS4, encodes a protein with homology to a human protein involved in DNA mismatch repair. MMS4 is an essential protein in yeast, and the product of this gene is needed for normal DNA replication and for cell viability after exposure to DNA-damaging agents such as MMS. The long-term goal of this study is to elucidate the molecular nature of MMS4 and of the other genes identified in the yeast screen. In the first part of the proposal, the following studies will be undertaken: (1) identify the sites in the MMS4 protein that are responsible for the essential nature of the protein; (2) determine whether the MMS4 protein is involved in DNA replication; (3) determine whether MMS4 is required for the proper repair of

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