The ultimate goal of studies in our laboratory is to understand the function of telomeres, the specialized protein-DNA structures present at the end of the chromosome using the simple eukaryote Saccharomyces cerevisiae as a model system. The medical relevance of the control of the simple sequence size present at the telomere has been underscored by accumulating evidence linking both the loss of telomeric sequences with cellular senescence, and the activation of the enzyme responsible for telomere addition, telomerase, with cell immortalization and malignancy. Overly long telomeres also lead to high rates of cell death. The focus of studies in this proposal is on a telomeric processing event recently characterized in our laboratory. This process termed telomeric rapid deletion (TRD) is capable of returning over-elongated telomeres to wild type length in a single-step process. This process appears to involve two steps: a) the pairing between the telomeres of heterologous chromosomes and b) intrachromatid excision of the over-elongated telomere. The characteristics of TRD suggest that it may play an important role in the regulation of telomere size. Similar rapid deletion events have been observed in human cell lines (and numerous other organisms), where they may contribute to the formation of aberrant clonal derivatives, associated with numerous disease states. Four goals are proposed to further understand this critical process. First, mutants isolated in our laboratory that have differing effects on TRD and telomere size control will be phenotypically characterized, and the corresponding genes cloned and characterized. Second, the role of both telomeric chromatin structure and of DNA damage in TRD will be evaluated. Third, several approaches will be taken to test the role of telomere-telomere pairing on TRD. Finally, the telomere will be physically marked with restriction endonuclease sites to provide a physical monitor for rapid deletion events. A combination of these four approaches will lead to a significant advance in understanding the mechanism of TRD.
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| Bucholc, M; Park, Y; Lustig, A J (2001) Intrachromatid excision of telomeric DNA as a mechanism for telomere size control in Saccharomyces cerevisiae. Mol Cell Biol 21:6559-73 |
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