Mechanism of increase genomic instability in aging yeast

老化酵母基因组不稳定性增加的机制

• 批准号: 7061665
• 负责人: Daniel E. Gottschling
• 金额: $ 32.54万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7061665
• 关键词: Saccharomyces cerevisiae; age difference; aging; alleles; biological signal transduction; chromosomes; fungal genetics; gene expression; gene mutation; genetic mapping; loss of heterozygosity; microarray technology; polymerase chain reaction; suppressor mutations; technology /technique development

DESCRIPTION (provided by applicant): Age is the greatest carcinogen, yet the mechanism by which the incidence of cancer dramatically increases as humans age is unclear. In an effort to better understand this phenomenon, we have sought to develop a system in the yeast, Saccharomyces cerevisiae that shows one of the hallmarks of cancer - genomic instability - as a function of cellular age. Specifically, we examined the relationship between aging and genomic instability by monitoring loss of heterozygosity (LOH) on two different chromosomes during replicative aging in yeast. We discovered that aging yeast mother cells underwent a switch to a nearly 100-fold increase in LOH in their progeny. After the switch, the increased rate of LOH remained constant throughout the remainder of the lifespan. Extending lifespan did not alter the onset nor frequency of age-induced LOH, suggesting that the aging "clock" that sets off hyper-LOH is distinct from that which regulated replicative lifespan. Furthermore, age-induced LOH is qualitatively distinct; in young cells LOH proceeds primarily by reciprocal recombination, whereas in old cells it is non-reciprocal and proceeds by break-induced replication with a striking daughter cell bias. We now propose to use the powerful collection of resources and tools available in S. cerevisiae to develop our understanding about age-induced LOH. We anticipate that genes and processes identified in this analysis will lead us to a molecular understanding of how genomic instability increases in aging yeast cells. These may then serve as means to identify genes and processes in human cells that become defective with age and ultimately lead to aging-dependent diseases such as cancer.

描述（由申请人提供）：年龄是最大的致癌物，然而随着人类年龄的增长，癌症发病率急剧增加的机制尚不清楚。为了更好地理解这一现象，我们试图在酵母（酿酒酵母）中开发一种系统，该系统显示出癌症的标志之一——基因组不稳定性——作为细胞年龄的函数。具体来说，我们通过监测酵母在复制衰老过程中两条不同染色体的杂合性损失（LOH）来研究衰老与基因组不稳定性之间的关系。我们发现，衰老的酵母母细胞在其后代中经历了LOH增加近100倍的转变。切换后，在剩余的使用寿命中，LOH的增长率保持不变。延长寿命并没有改变年龄引起的LOH的发病和频率，这表明引发hyper-LOH的衰老“时钟”与调节复制寿命的“时钟”不同。此外，年龄诱导的LOH在质量上是不同的；在年轻细胞中，LOH主要通过相互重组进行，而在年老细胞中，LOH是非相互的，通过断裂诱导进行