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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Genetics Study Section (GEN)
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Anderson, Richard A
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
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Moore, Anthony; Dominska, Margaret; Greenwell, Patricia et al. (2018) Genetic Control of Genomic Alterations Induced in Yeast by Interstitial Telomeric Sequences. Genetics 209:425-438
Kiktev, Denis A; Sheng, Ziwei; Lobachev, Kirill S et al. (2018) GC content elevates mutation and recombination rates in the yeast Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 115:E7109-E7118
Zhang, Ke; Wu, Xue-Chang; Zheng, Dao-Qiong et al. (2017) Effects of Temperature on the Meiotic Recombination Landscape of the Yeast Saccharomyces cerevisiae. MBio 8:
Zhao, Ying; Dominska, Margaret; Petrova, Aleksandra et al. (2017) Properties of Mitotic and Meiotic Recombination in the Tandemly-Repeated CUP1 Gene Cluster in the Yeast Saccharomyces cerevisiae. Genetics 206:785-800
Omer, Sumita; Lavi, Bar; Mieczkowski, Piotr A et al. (2017) Whole Genome Sequence Analysis of Mutations Accumulated in rad27? Yeast Strains with Defects in the Processing of Okazaki Fragments Indicates Template-Switching Events. G3 (Bethesda) 7:3775-3787
Yin, Yi; Dominska, Margaret; Yim, Eunice et al. (2017) High-resolution mapping of heteroduplex DNA formed during UV-induced and spontaneous mitotic recombination events in yeast. Elife 6:
Andersen, Sabrina L; Zhang, Aimee; Dominska, Margaret et al. (2016) High-Resolution Mapping of Homologous Recombination Events in rad3 Hyper-Recombination Mutants in Yeast. PLoS Genet 12:e1005938
Zheng, Dao-Qiong; Zhang, Ke; Wu, Xue-Chang et al. (2016) Global analysis of genomic instability caused by DNA replication stress in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A 113:E8114-E8121
Clausen, Anders R; Lujan, Scott A; Burkholder, Adam B et al. (2015) Tracking replication enzymology in vivo by genome-wide mapping of ribonucleotide incorporation. Nat Struct Mol Biol 22:185-91
O'Connell, Karen; Jinks-Robertson, Sue; Petes, Thomas D (2015) Elevated Genome-Wide Instability in Yeast Mutants Lacking RNase H Activity. Genetics 201:963-75

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