Genetic regulation of genome stability in yeast

描述(申请人提供)：在哺乳动物中，两个相关基因，atm和 AIR，编码与基因组维持有关的非常大的蛋白激酶 稳定性。ATM基因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，而且细胞 AT患者来源的DNA对DNA损伤剂非常敏感。在……里面 此外，AT细胞的染色体具有短的端粒；超重组和 染色体断裂也与ATM和ATR的突变有关。这个 酿酒酵母有两个基因，Tell和Mec1，它们是 在结构和功能上与自动柜员机和自动柜员机相关。带有Tell的酵母菌株 Mec1突变具有遗传不稳定性，这与哺乳动物中观察到的情况类似 ATM或ATR中有突变的细胞：染色体的高频率 重排和染色体丢失，一种强烈的突变体表型，丢失 端粒序列和细胞衰老。 总体目标是了解Tell Mec1菌株的遗传不稳定性。 这项提案的一些具体目标是：1)描述 在Tell Mec1中产生染色体异常的机制 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 Mec1蛋白影响端粒结构；4)确定与生物相关的 Tell p和Mec1 p激酶活性的底物；以及5)使用遗传 筛选与Tell p和Mecip相互作用的蛋白质。对于许多人来说 在这些研究中，在Tell MED1菌株中观察到的表型将与 在缺乏端粒酶的菌株中发现这些基因，因为菌株缺乏端粒酶 也会经历细胞衰老。

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.