title: Natural polymorphism in BUL2 links cellular amino acid availability with chronological aging and telomere maintenance in yeast.
abstract: 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.
authors: Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors: Elizabeth X
authors: EX
authors: Kwan
authors: Eric
authors: E
authors: Foss
authors: Leonid
authors: L
authors: Kruglyak
authors: Antonio
authors: A
authors: Bedalov
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000375:Aging / Q000235:genetics*; D000595:Amino Acid Sequence; D026905:Amino Acid Transport Systems / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D040641:Quantitative Trait Loci; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism*; D016615:Telomere / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D026905:Amino Acid Transport Systems; D000596:Amino Acids; C117205:BUL2 protein, S cerevisiae; C071664:GLN3 protein, S cerevisiae; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C107277:Wtm1 protein, S cerevisiae; D012264:Ribonucleotide Reductases; C551024:Rnr1 protein, S cerevisiae; D043743:Ubiquitin-Protein Ligase Complexes