Telomeres, the structures found at the ends of linear chromosomes, are essential for genomic stability and normal cellular growth. The past last few years has seen an explosive interest in the possibility that telomere length regulation is involved in the related processes of aging and cancer. Therefore, a complete understanding of the components that are required for normal telomere function is necessary, in order to address the consequences of telomere dysfunction in abnormal cells. Telomere function in both yeast and human cells requires factors that are essential for maintaining the integrity of the chromosome terminus, since loss ol chromosome end protection is immediately lethal for the cell. In addition, the enzyme telomerase, which is responsible for replicating the ends of chromosomes, is necessary for long term cellular proliferation. In yeast, the single-strand telomere binding protein Cdc 13 is critical for both telomere end protection and telomere replication: certain mutations in CDC13 result in extensive degradation of the end of the chromosome, whereas other mutations in Cdcl3 prevent telomerase access to the telomere. This application proposes an inter-related set of experiments designed to analyze the dual role of CDCI 3 in these two processes. Both genetic and biochemical experiments will be used to identify other proteins that function in combination with Cdcl3 to protect the telomere; such experiments also have the potential to identify the activity(s) that are responsible for degrading unprotected telomeres. In parallel, a set of experiments is presented to analyze how telomerase is recruited to the chromosome by Cdcl3, with a focus on the behavior of two proteins that mediate how Cdcl3 regulates telomerase access to the telomere. Characterization of the dual nature of this essential yeast telomere protein may serve as a paradigm for similar events at mammalian telomeres.
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