In mammals, two related genes, ATM and AIR, encode very large protein kinases involved in the maintenance of genome stability. Patients with mutations in ATM develop the neurodegenerative disease ataxia telangiectasia (AT). AT patients are very cancer-prone, and cells derived from AT patients are very sensitive to DNA damaging agents. In addition, chromosomes of AT cells have short telomeres; hyper-recombination and chromosome breakage are also associated with mutations in ATM and ATR. The yeast Saccharomyces cerevisiae has two genes, TELl and MEC1 that are structurally and functionally related to ATM and ATR. Yeast strains with tell mec1 mutations have genetic instability that mimics that observed in mammalian cells that have mutations in ATM or ATR: high frequencies of chromosome rearrangements and chromosome loss, a strong mutator phenotype, loss of telomeric sequences, and cellular senescence. The general goal is to understand the genetic instability of tell mec1 strains. Some of the specific aims of this proposal are: 1) to characterize the mechanisms involved in generating chromosome aberrations in the tell mec1 strain; 2) to determine whether the production of chromosome aberrations is causally linked to cellular senescence; 3) to determine whether the Tell and/or Mec1 proteins affect telomere structure; 4) to define the biologically-relevant substrates of the Tell p and Mec1 p kinase activities; and 5) to use genetic screens to identify proteins that interact with Tell p and Mecip. For many of these studies, the phenotypes observed in tell med1 strains will be compared to those found in strains lacking telomerase, since strains lacking telomerase also undergo cellular senescence.
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