Chronological Age-Dependent Genomic Instability in Yeast

描述（由申请人提供）：衰老是许多人类癌症的主要危险因素。然而，衰老对肿瘤发病率影响的机制尚不清楚，部分原因是很少有模型系统可用于研究年龄依赖性基因组不稳定性。此外，DNA突变在“正常衰老”和“寿命延长”中的作用尚不清楚。我们将验证组蛋白去乙酰化酶Sir2、信号转导蛋白Ras和Sch9协同调节酿酒酵母衰老和基因组不稳定性的假设。我们认为Sir2、Sch9和Ras2对时间顺序寿命和基因组不稳定性的影响部分是由修复DNA的酶的下调介导的。最后，我们将测试不同的DNA修复系统在时间老化和寿命延长中的作用。我的实验室开发了一种新的方法来研究酵母的老化基于非分裂种群的生存（按时间顺序的寿命）。这个系统使我们能够确定酵母中调节寿命的两条途径：Ras和Sch9途径。值得注意的是，酵母的Ras2和Sch9与哺乳动物的Ras和Akt这两个主要的人类致癌基因在功能上是同源的。Akt也在调节秀丽隐杆线虫、果蝇和小鼠寿命的胰岛素样通路中发挥作用。因此，按时间顺序衰老的酿酒酵母可以作为一种模型来鉴定调节基因组不稳定性的基因，并了解哺乳动物中年龄依赖性DNA突变和癌症的机制。

DESCRIPTION (provided by applicant): Aging is the major risk factor for many human cancers. However, the mechanisms responsible for the effect of aging on tumor incidence are poorly understood, in part because few model systems are available to study age-dependent genomic instability . Furthermore, the role of DNA mutations in "normal aging" and "life span extension" is unclear. We will test the hypothesis that the histone deacetylase Sir2, and the signal transduction proteins Ras and Sch9 synergistically regulate aging and genomic instability in S. cerevisiae. We propose that the effect of Sir2, Sch9, and Ras2 on chronological life span and genomic instability is mediated in part by the down-regulation of enzymes that repair DNA. Finally, we will test the role of different DNA repair systems in chronological aging and life span extension. My laboratory has developed a novel method to study aging in yeast based on the survival of non-dividing populations (chronological life span). This system allowed us to identify two pathways that regulate longevity in yeast: the Ras and Sch9 pathways. Notably yeast Ras2 and Sch9 are functional homologs of mammalian Ras and Akt, two of the major human oncogenes. Akt also functions in insulin-like pathways that regulates longevity in C. elegans, Drosophila, and mice. Thus, chronologically aging S. cerevisiae can serve as a model to identify genes that regulate genomic instability and understand the mechanisms responsible for age-dependent DNA mutations and cancer in mammals.