Mechanism of increase genomic instability in aging yeast

描述（由申请人提供）：年龄是最大的致癌因素，但癌症发病率随着人类年龄的增长而急剧增加的机制尚不清楚。为了更好地理解这一现象，我们试图在酵母中开发一个系统，酿酒酵母，显示癌症的标志之一-基因组不稳定性-作为细胞年龄的函数。具体来说，我们研究了衰老和基因组不稳定性之间的关系，通过监测杂合性丢失（洛）在两个不同的染色体在复制老化的酵母。我们发现老化的酵母母细胞在其后代中经历了洛增加近100倍的转变。转换后，洛缺失的增加率在剩余的寿命中保持不变。 延长寿命并没有改变年龄诱导的洛缺失的发生和频率，这表明引发超洛缺失的衰老“时钟”与调节复制寿命的时钟不同。 此外，年龄诱导的洛在性质上是不同的;在年轻细胞中，洛主要通过相互重组进行，而在老年细胞中，它是非相互的，通过断裂诱导的重组进行。 具有显著的子细胞偏好的复制。 我们现在建议使用S.酿酒酵母，以发展我们对年龄诱导的洛缺失的理解。我们预计，在这项分析中确定的基因和过程将使我们从分子上了解衰老酵母细胞中基因组不稳定性如何增加。然后，这些可以作为识别人类细胞中随着年龄增长而变得有缺陷并最终导致衰老依赖性疾病（如癌症）的基因和过程的手段。

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.