Mechanism of increase genomic instability in aging yeast

描述(申请人提供)：年龄是最大的致癌物，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，我们试图在酿酒酵母中开发一种系统，该系统显示癌症的特征之一-基因组不稳定-作为细胞年龄的函数。具体地说，我们通过监测酵母复制老化过程中两条不同染色体上的杂合性丢失(LOH)来研究老化和基因组不稳定性之间的关系。我们发现，老化的酵母母细胞在其后代中经历了近100倍的LOH增加。在转换后，LOH增加的比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LOH的开始或频率，这表明引发高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在性质上是不同的；在年轻细胞中，LOH主要通过相互重组进行，而在老年细胞中，LOH是非相互的，通过断裂诱导进行。 具有明显的子细胞偏向的复制。我们现在建议使用酿酒酵母中可用的强大资源和工具来发展我们对年龄诱导的LOH的理解。我们预计，这一分析中确定的基因和过程将引导我们从分子上了解老化的酵母细胞中基因组不稳定性是如何增加的。然后，这些基因可以作为识别人类细胞中随着年龄增长而变得有缺陷的基因和过程的手段，最终导致癌症等与衰老相关的疾病。

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.