Chronological Age-Dependent Genomic Instability in Yeast

酵母中随年龄变化的基因组不稳定性

• 批准号: 7096237
• 负责人: VALTER D. LONGO
• 金额: $ 30.83万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7096237
• 关键词: DNA damage; DNA repair; Saccharomyces cerevisiae; aging; amidohydrolases; caloric dietary content; cell growth regulation; enzyme induction /repression; fungal genetics; fungal proteins; gene environment interaction; gene interaction; gene mutation; genetic regulation; guanine nucleotide binding protein; longevity; microarray technology; microorganism culture; microorganism growth; microorganism population study; nutrient requirement; oncogenes; protein kinase; protein protein interaction; protooncogene; stress

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.

描述（由申请人提供）：衰老是许多人类癌症的主要危险因素。但是，对衰老对肿瘤发病率的影响的机制知之甚少，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。我们将检验以下假设：塞氏链球菌中的组蛋白脱乙酰基酶SIR2以及信号转导蛋白RAS和SCH9协同调节衰老和基因组不稳定性。我们建议SIR2，SCH9和RAS2对年代寿命和基因组不稳定性的影响部分是由于修复DNA的酶的下调而介导。最后，我们将测试不同DNA修复系统在年代老化和寿命延长中的作用。我的实验室已经开发了一种新的方法，可以根据非分散种群的生存（年代生命跨度）研究酵母的衰老。该系统使我们能够确定调节酵母中寿命的两种途径：RAS和SCH9途径。值得注意的是，酵母RAS2和SCH9是哺乳动物Ras和Akt的功能同源物，这是两个主要的人类癌基因。 AKT还起作用在胰岛素样途径中起作用，可调节秀丽隐杆线虫，果蝇和小鼠的寿命。因此，按时间顺序老化的酿酒酵母可以用作鉴定调节基因组不稳定性的基因，并了解哺乳动物中依赖年龄依赖性DNA突变和癌症的机制。