Telomeres are the ends of linear eukaryotic chromosomes. These structures are important for the replication and maintenance of chromosome ends. Loss of telomere function is thought to cause chromosome fusions, leading to chromosome breakage, gene amplification and chromosome loss. In many organisms, the terminal domain of the chromosome consists of short repeated sequences: G3T2A in humans, G4T4 in the ciliate Oxytricha and G1- 3T in the yeast Saccharomyces cerevisiae. Current evidence suggests that telomere function is carried out by these repeats and the proteins that bind to them. Understanding how these repeats are maintained is fundamental to understanding chromosome integrity and stability. The number of these repeats, or telomere length, appears to be regulated. For example, Oxytricha telomeres have a defined structure. We have evidence that yeast telomere length is regulated and have cloned the gene for a potential regulator, TEL2. In humans, telomeres in somatic cells shorten as cell divide. Work in several labs has led to a telomere length checkpoint hypothesis where cells senesce when telomeres become too short. This hypothesis implies some form of telomere length measurement and regulation. The long term goal of this proposal is to understand telomere length regulation in yeast so that it may be used as a paradigm for regulation in other organisms. The TEL2 gene appears to be a regulator of yeast telomere length. The tel2-1 mutation causes cells to maintain short telomeres and blocks telomere lengthening. The TEL2 gene is essential for life, and the structure of the gene suggests that it may be translationally controlled. Another gene that affects yeast telomere length, EST1, has a similar structure. The proposed research will develop a firm understanding of telomere length control by l) determining how TEL2 protein functions in the cell; 2) identifying new potential telomere length regulators; and 3) determining if genes affecting telomere length are under co-ordinate translational control. TEL2 function will be investigated by studying this gene's expression, generating new tel2 mutations to test our models of TEL2 function, and to investigate the biochemical properties and subcellular location of TEL2 protein. Potential telomere length regulators will be identified by isolating mutations that alter telomere length. The isolation of these mutations is based on the phenotypes of existing telomere length mutants. Finally, the possibility of translational control of TEL2 and EST1 expression will be tested by altering their mRNAs and monitoring TEL2 and EST1 protein levels under different conditions. The results from this research will increase our understanding of how yeast telomere length is measured and regulated and provide models for testing the telomere length checkpoint hypothesis in the human system.

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Molecular Cytology Study Section (CTY)
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Cleveland Clinic Lerner
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