Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York, United States of America.
PLoS One. 2007 Aug 15;2(8):e748. doi: 10.1371/journal.pone.0000748.
The chronological lifespan of eukaryotic organisms is extended by the mutational inactivation of conserved growth-signaling pathways that regulate progression into and through the cell cycle. Here we show that in the budding yeast S. cerevisiae, these and other lifespan-extending conditions, including caloric restriction and osmotic stress, increase the efficiency with which nutrient-depleted cells establish or maintain a cell cycle arrest in G1. Proteins required for efficient G1 arrest and longevity when nutrients are limiting include the DNA replication stress response proteins Mec1 and Rad53. Ectopic expression of CLN3 encoding a G1 cyclin downregulated during nutrient depletion increases the frequency with which nutrient depleted cells arrest growth in S phase instead of G1. Ectopic expression of CLN3 also shortens chronological lifespan in concert with age-dependent increases in genome instability and apoptosis. These findings indicate that replication stress is an important determinant of chronological lifespan in budding yeast. Protection from replication stress by growth-inhibitory effects of caloric restriction, osmotic and other stresses may contribute to hormesis effects on lifespan. Replication stress also likely impacts the longevity of higher eukaryotes, including humans.
真核生物的时序寿命通过使调节细胞周期进入和通过的保守生长信号通路发生突变失活而延长。在这里，我们表明，在酿酒酵母 S. cerevisiae 中，这些和其他延长寿命的条件，包括热量限制和渗透压应激，增加了营养缺乏细胞建立或维持细胞周期 G1 阻滞的效率。在营养有限时，需要有效的 G1 阻滞和长寿的蛋白包括 DNA 复制应激反应蛋白 Mec1 和 Rad53。在营养耗尽期间下调的 G1 周期蛋白 CLN3 的异位表达增加了营养缺乏细胞在 S 期而不是 G1 期停止生长的频率。CLN3 的异位表达也与随着年龄增长的基因组不稳定性和细胞凋亡一起缩短了时序寿命。这些发现表明，复制应激是芽殖酵母时序寿命的一个重要决定因素。通过热量限制、渗透压和其他应激的生长抑制作用来保护免受复制应激可能有助于对寿命的激素作用。复制应激也可能影响包括人类在内的高等真核生物的寿命。
