Natural polymorphism in BUL2 links cellular amino acid availability with chronological aging and telomere maintenance in yeast.
Natural polymorphism in BUL2 links cellular amino acid availability with chronological aging and telomere maintenance in yeast.
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DOI：
10.1371/journal.pgen.1002250
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发表时间：
2011-08
期刊：
影响因子：
4.5
通讯作者：
Bedalov A
中科院分区：
文献类型：
--
作者：
Kwan EX;Foss E;Kruglyak L;Bedalov A
衰老和长寿被认为是高度复杂的遗传性状。为了深入了解衰老作为一种多基因性状，我们采用了远交酿酒酵母模型，通过杂交葡萄园菌株RM11和实验室菌株S288c，以确定控制时间寿命的数量性状基因座。在这个交叉中，调节时间寿命的主要基因座中，发现一个遗传连锁与先前绘制的控制端粒长度变化的基因座一致。我们发现，一个单核苷酸多态性的BUL2，编码一个组件的泛素连接酶复合物参与运输的氨基酸渗透酶，控制按时间顺序的寿命和端粒长度以及氨基酸摄取。由BUL2多态性引起的细胞氨基酸利用率变化通过调节转录因子Gln3的活性改变端粒长度。在与这种表型相关的GLN3转录靶点中，我们确定了Wtm1，其上调促进核糖核苷酸还原酶（RNR）组分的核保留，并抑制S期RNR酶复合物的组装。RNR的抑制是Gln3调节端粒长度的机制之一。在这个远交酵母群体中的BUL2多态性的鉴定揭示了细胞氨基酸可用性、按时间顺序的寿命和端粒长度控制之间的联系。饮食限制促进许多物种的长寿，从酵母到灵长类动物，并延迟与衰老相关的病理学，包括啮齿动物模型中的癌症。有相当大的兴趣了解营养限制如何介导这些有益的影响。我们对衰老遗传学的了解大部分来自对等基因模式生物的研究，其中单个基因变化的影响可以独立于其他遗传改变进行检查。为了探索更广泛的遗传变异谱，并深入了解衰老相关的表型作为多基因性状，我们分析了122 S的时间寿命。酿酒酵母菌株来自实验室和葡萄园酵母菌株之间的交叉。控制时间寿命的主要遗传位点被发现与以前绘制的控制端粒长度的基因座相同。在BUL2中，一个参与控制氨基酸渗透酶的基因，负责多态性的鉴定，使我们能够建立一个以前未被认识到的细胞氨基酸摄入量，时间老化和端粒维持之间的联系。虽然人类流行病学研究已经将端粒缩短与死亡率增加联系起来，但尚不清楚这些过程是如何联系起来的。我们的研究结果表明，在酵母中，减少氨基酸的摄取和随之而来的减少营养信号延长时间寿命，但减少端粒长度。
Aging and longevity are considered to be highly complex genetic traits. In order to gain insight into aging as a polygenic trait, we employed an outbred Saccharomyces cerevisiae model, generated by crossing a vineyard strain RM11 and a laboratory strain S288c, to identify quantitative trait loci that control chronological lifespan. Among the major loci that regulate chronological lifespan in this cross, one genetic linkage was found to be congruent with a previously mapped locus that controls telomere length variation. We found that a single nucleotide polymorphism in BUL2, encoding a component of an ubiquitin ligase complex involved in trafficking of amino acid permeases, controls chronological lifespan and telomere length as well as amino acid uptake. Cellular amino acid availability changes conferred by the BUL2 polymorphism alter telomere length by modulating activity of a transcription factor Gln3. Among the GLN3 transcriptional targets relevant to this phenotype, we identified Wtm1, whose upregulation promotes nuclear retention of ribonucleotide reductase (RNR) components and inhibits the assembly of the RNR enzyme complex during S-phase. Inhibition of RNR is one of the mechanisms by which Gln3 modulates telomere length. Identification of a polymorphism in BUL2 in this outbred yeast population revealed a link among cellular amino acid availability, chronological lifespan, and telomere length control. Dietary restriction promotes longevity in many species, ranging from yeast to primates, and delays aging-related pathologies including cancer in rodent models. There is considerable interest in understanding how nutrient limitation mediates these beneficial effects. Much of what we have learned about the genetics of aging comes from studying isogenic model organisms, where the effects of single gene changes can be examined independently of other genetic alterations. In order to explore a broader spectrum of genetic variation and to gain insight into aging-related phenotypes as polygenic traits, we analyzed the chronological lifespan of 122 S. cerevisiae strains derived from a cross between laboratory and vineyard yeast strains. The major genetic locus controlling chronological lifespan was found to be identical to a previously mapped locus that controls telomere length. Identification of the responsible polymorphism in BUL2, a gene involved in controlling amino acid permeases, allowed us to establish a previously unrecognized link among cellular amino acid intake, chronological aging, and telomere maintenance. While human epidemiological studies have linked shortened telomeres with increased mortality, it is unclear how these processes are connected. Our results suggest that, in yeast, reduced amino acid uptake and consequent reduced nutrient signaling extend chronological lifespan but reduce telomere length.
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