Genetic regulation of genome stability in yeast

描述（由申请人提供）：在哺乳动物中，两个相关基因ATM和 AIR，编码参与基因组维持的非常大的蛋白激酶 稳定ATM突变的患者会患上神经退行性疾病， 共济失调毛细血管扩张症（AT）。AT患者非常容易患癌症， 来源于AT患者的细胞对DNA损伤剂非常敏感。在 此外，AT细胞的染色体具有短端粒;超重组和 染色体断裂也与ATM和ATR的突变有关。的 酿酒酵母具有两个基因TEL 1和MEC 1， 在结构和功能上与ATM和ATR相关。具有tell的酵母菌株 mec 1突变具有遗传不稳定性，类似于在哺乳动物中观察到的 在ATM或ATR中有突变的细胞：高频率的染色体 重排和染色体丢失，强突变表型， 端粒序列和细胞衰老。 总体目标是了解tell mec 1菌株的遗传不稳定性。 这项建议的一些具体目标是：1）描述 tell mec 1中产生染色体畸变的机制 菌株; 2）确定染色体畸变的产生是否 与细胞衰老有因果关系; 3）确定Tell和/或 Mec 1蛋白影响端粒结构; 4）定义生物相关的 Tell p和Mec 1 p激酶活性的底物;以及5）使用遗传学方法， 筛选出与Tell p和Mecip相互作用的蛋白质。对于许多 在这些研究中，在tell med 1菌株中观察到的表型将与 这些在缺乏端粒酶的菌株中发现，因为缺乏端粒酶的菌株 也经历细胞衰老。

DESCRIPTION (provided by applicant): 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.