Aging in wild and laboratory yeast: nutrient sensing, telomeres, and the nucleolus.
Kwan, Elizabeth X.
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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 <italic>Saccharomyces cerevisiae</italic> model, generated by crossing a vineyard strain (RM11-1a) and a laboratory strain (S288c), to identify quantitative trait loci that control chronological lifespan, replicative lifespan, and telomere length. 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 <italic>BUL2</italic>, 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 <italic>BUL2</italic> polymorphism alter telomere length by modulating activity of a transcription factor Gln3. Among the <italic>GLN3</italic> 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. Thus, identification of a polymorphism in <italic>BUL2</italic> in this outbred yeast population revealed a previously unknown link between cellular amino acid availability, chronological lifespan and telomere length control. A genome scan for loci that control replicative lifespan identified the rDNA as a major quantitative trait locus, accounting for 45% of the genetic variation in lifespan. Despite its large size, rDNA is inherited as a single genetic locus due to the virtual absence of meiotic recombination. The lifespan extension conferred by the vineyard rDNA was independent of Sir2 and Fob1, proteins known to be involved in rDNA metabolism and replicative lifespan. Among the rDNA sequence differences between the two strains, we identified a polymorphism in the rDNA origin of replication in the vineyard strain, which leads to a marked decrease in origin activation in plasmid maintenance assays as compared to the laboratory sequence, is responsible for lifespan extension. We also found that vineyard rDNA has markedly reduced size compared to laboratory rDNA and that strains carrying vineyard rDNA have increased capacity for replication initiation at weak origins both in the genome and on plasmids. Our results suggest that rDNA origin activation alters DNA replication dynamics which modulates replicative lifespan.