Telomeres protect chromosome ends and allow for chromosome length maintenance. Telomerase is the enzyme that maintains telomeres by the addition of telomere repeat sequences onto chromosome ends. Inactivating telomerase activity leads to progressive telomere shortening and loss of telomere function. Many human cells do not express telomerase and telomeres shorten throughout their lifespan. For cells with a limited requirement for division, this shortening has no consequence. However, most tumor cells reactivate telomerase to allow for continued growth. Telomerase is thus a target for cancer therapy as inhibition of telomerase should lead to telomere dysfunction and cell death. We are using yeast to dissect the details of the consequences of telomerase inactivation. Short telomeres lead to both an increase in genetic instability and to cell cycle arrest and, in mammalian cells, to apoptosis. In recent work we found that non-reciprocal translocations occur frequently in yeast cells that lack telomerase. Such non reciprocal translocations are frequently found in tumors and may be a major mechanism for loss of heterozygosity. Here we propose experiments designed to determine the molecular events that initiate these translocations. In addition to chromosomal rearrangements, we found that loss of telomere function leads to a cell cycle checkpoint arrest in yeast. This arrest requires components of the DNA damage response pathway. In the next several years we will investigate this response pathway and determine whether there are mechanisms that specifically recognize telomere dysfunction.
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