Department of Anatomy and Cell Biology, The University of Western Ontario, London, ON N6A 5C1, Canada.
Department of Biochemistry, The University of Western Ontario, London, ON N6A 5C1, Canada.
G3 (Bethesda). 2023 Jan 12;13(1). doi: 10.1093/g3journal/jkac287.
Gene expression undergoes considerable changes during the aging process. The mechanisms regulating the transcriptional response to cellular aging remain poorly understood. Here, we employ the budding yeast Saccharomyces cerevisiae to better understand how organisms adapt their transcriptome to promote longevity. Chronological lifespan assays in yeast measure the survival of nondividing cells at stationary phase over time, providing insights into the aging process of postmitotic cells. Tra1 is an essential component of both the yeast Spt-Ada-Gcn5 acetyltransferase/Spt-Ada-Gcn5 acetyltransferase-like and nucleosome acetyltransferase of H4 complexes, where it recruits these complexes to acetylate histones at targeted promoters. Importantly, Tra1 regulates the transcriptional response to multiple stresses. To evaluate the role of Tra1 in chronological aging, we took advantage of a previously characterized mutant allele that carries mutations in the TRA1 PI3K domain (tra1Q3). We found that loss of functions associated with tra1Q3 sensitizes cells to growth media acidification and shortens lifespan. Transcriptional profiling reveals that genes differentially regulated by Tra1 during the aging process are enriched for components of the response to stress. Notably, expression of catalases (CTA1, CTT1) involved in hydrogen peroxide detoxification decreases in chronologically aged tra1Q3 cells. Consequently, they display increased sensitivity to oxidative stress. tra1Q3 cells are unable to grow on glycerol indicating a defect in mitochondria function. Aged tra1Q3 cells also display reduced expression of peroxisomal genes, exhibit decreased numbers of peroxisomes, and cannot grow on media containing oleate. Thus, Tra1 emerges as an important regulator of longevity in yeast via multiple mechanisms.
基因表达在衰老过程中会发生很大的变化。调节细胞衰老转录反应的机制仍知之甚少。在这里，我们利用 budding yeast Saccharomyces cerevisiae 来更好地理解生物体如何调整其转录组以促进长寿。酵母的时序寿命测定法测量非分裂细胞在静止期随时间的存活情况，为了解有丝分裂后细胞的衰老过程提供了线索。Tra1 是酵母 Spt-Ada-Gcn5 乙酰转移酶/Spt-Ada-Gcn5 乙酰转移酶样和核小体乙酰转移酶 H4 复合物的必需组成部分，在那里它招募这些复合物在靶向启动子处乙酰化组蛋白。重要的是，Tra1 调节对多种应激的转录反应。为了评估 Tra1 在时序老化中的作用，我们利用了先前表征的携带 TRA1 PI3K 结构域突变的突变等位基因（tra1Q3）。我们发现，与 tra1Q3 相关的功能丧失会使细胞对生长培养基酸化敏感并缩短寿命。转录谱分析显示，在衰老过程中受 Tra1 差异调控的基因富集了应激反应的成分。值得注意的是，过氧化氢解毒涉及的过氧化氢酶（CTA1、CTT1）的表达在时序老化的 tra1Q3 细胞中下降。因此，它们对氧化应激的敏感性增加。tra1Q3 细胞无法在甘油上生长，表明线粒体功能缺陷。老化的 tra1Q3 细胞也显示过氧化物酶体基因表达减少，过氧化物酶体数量减少，并且不能在含有油酸的培养基上生长。因此，Tra1 通过多种机制成为酵母中长寿的重要调节剂。
