The loss of telomeric DNA in human somatic cells, arising from of the lack of telomerase expression, causes cellular senescesce and is associated with aging. Escaping the normal consequences of telomere loss is a critical step in the progression of cancer. Thus, understanding the normal mechanisms of cellular response to telomere loss and mechanisms that bypass the normal response are important for understanding, and possibly treating, cancer and ailments associated with aging. This work will use the model organism Drosophila melanogaster to investigate these issues. Preliminary experiments show that the response of Drosophila cells to telomere loss is very similar of the response of human cells to telomere loss, and is likely to be highly informative. There are 4 primary goals of this work. The first goal is to quantitatively characterize the response of Drosophila somatic cells to loss of a single telomere. A method for tracking the fate of cells that have lost a telomere will be implemented for this purpose. Second, the genetic control of these responses will be investigated. The third goal is to determine the mechanism of response of male germline cells, in which the non-telomeric chromosome ends are efficiently healed. The final goal is to investigate the nature of the healed chromosomes, to determine whether the telomeres they posses provide a normal protective function to the end of the chromosomes, or whether they are only partially functional. These investigations will provide an understanding of the machinery used to recognize telomere loss and to direct the response of cells to such loss. The differences between somatic and germline cells may provide insight into similar differences found in human cells. ? ? ?
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