Genome-wide screen in Saccharomyces cerevisiae identifies vacuolar protein sorting, autophagy, biosynthetic, and tRNA methylation genes involved in life span regulation.
Genome-wide screen in Saccharomyces cerevisiae identifies vacuolar protein sorting, autophagy, biosynthetic, and tRNA methylation genes involved in life span regulation.
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DOI：
10.1371/journal.pgen.1001024
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发表时间：
2010-07-15
期刊：
影响因子：
4.5
通讯作者：
Longo VD
中科院分区：
文献类型：
--
作者：
Fabrizio P;Hoon S;Shamalnasab M;Galbani A;Wei M;Giaever G;Nislow C;Longo VD
对酿酒酵母（Saccharomycescerevisiae）的按时间顺序的寿命的研究，测量了非分裂酵母菌群的存活率，已经鉴定了促进从酵母到哺乳动物的生物体衰老的同源基因和途径。使用竞争性全基因组方法，我们对一整套约4,800个可行的缺失突变体进行了筛选，以确定增加或减少实足寿命的基因。一半的假定的短/长寿命的突变体重新测试的初步筛选得到证实，证明了我们的方法的实用性。参与液泡蛋白分选、自噬和线粒体功能的基因的缺失缩短了寿命，证实了呼吸和降解过程对长期生存至关重要。在缺失显著延长寿命的基因中，ACB 1、CKA 2和TRM 9分别涉及脂肪酸转运和生物合成、细胞信号传导和tRNA甲基化。这些基因的缺失赋予了热休克抗性，支持在几种模式生物中观察到的寿命延长和细胞保护之间的联系。这些新的酵母寿命决定因素在其他物种中的高度保守性提高了它们在衰老中的作用可能是保守的。模式生物有助于揭示控制寿命的基因，并确定其在衰老中的作用在进化上遥远的单细胞酵母和小鼠之间保守的分子途径。由于酵母特别适合于遗传学和基因组学研究，它们已被广泛用作衰老研究的模型系统。在这里，我们已经利用了一个强大的基因组工具，酵母缺失收集，筛选池的非必需的缺失突变体（约4,800），以确定新的基因参与调节酵母的时间寿命。我们的研究结果表明，正常的寿命取决于功能性线粒体和细胞通过自噬降解细胞成分和蛋白质的能力。我们的数据表明，细胞信号蛋白，CK 2，和不同的细胞过程，如脂肪酸代谢，氨基酸生物合成，和tRNA修饰调节酵母时序老化。在这项研究中发现的新的寿命调节基因的高度保守性表明，它们在寿命调节中的作用可能是保守的高等真核生物。
The study of the chronological life span of Saccharomyces cerevisiae, which measures the survival of populations of non-dividing yeast, has resulted in the identification of homologous genes and pathways that promote aging in organisms ranging from yeast to mammals. Using a competitive genome-wide approach, we performed a screen of a complete set of approximately 4,800 viable deletion mutants to identify genes that either increase or decrease chronological life span. Half of the putative short-/long-lived mutants retested from the primary screen were confirmed, demonstrating the utility of our approach. Deletion of genes involved in vacuolar protein sorting, autophagy, and mitochondrial function shortened life span, confirming that respiration and degradation processes are essential for long-term survival. Among the genes whose deletion significantly extended life span are ACB1, CKA2, and TRM9, implicated in fatty acid transport and biosynthesis, cell signaling, and tRNA methylation, respectively. Deletion of these genes conferred heat-shock resistance, supporting the link between life span extension and cellular protection observed in several model organisms. The high degree of conservation of these novel yeast longevity determinants in other species raises the possibility that their role in senescence might be conserved. Model organisms have been instrumental in uncovering genes that function to control life span and to identify the molecular pathways whose role in aging is conserved between the evolutionarily distant unicellular yeast and mice. Because yeast are particularly amenable to genetics and genomics studies, they have been used widely as model system for aging research. Here we have exploited a powerful genomic tool, the yeast deletion collection, to screen a pool of non-essential deletion mutants (∼4,800) to identify novel genes involved in the regulation of yeast chronological life span. Our results show that normal life span depends on functional mitochondria and on the cell's ability to degrade cellular components and proteins by autophagy. Our data indicate that a cell signaling protein, CK2, and diverse cellular processes such as fatty acid metabolism, amino acid biosynthesis, and tRNA modification modulate yeast chronological aging. The high level of conservation of the novel life span regulatory genes uncovered in this study suggests that their role in longevity regulation might be conserved in higher eukaryotes.
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