title: The Levels of a Universally Conserved tRNA Modification Regulate Cell Growth.
abstract: N(6)-Threonylcarbamoyl-adenosine (t(6)A) is a universal modification occurring at position 37 in nearly all tRNAs that decode A-starting codons, including the eukaryotic initiator tRNA (tRNAi (Met)). Yeast lacking central components of the t(6)A synthesis machinery, such as Tcs3p (Kae1p) or Tcs5p (Bud32p), show slow-growth phenotypes. In the present work, we show that loss of the Drosophila tcs3 homolog also leads to a severe reduction in size and demonstrate, for the first time in a non-microbe, that Tcs3 is required for t(6)A synthesis. In Drosophila and in mammals, tRNAi (Met) is a limiting factor for cell and animal growth. We report that the t(6)A-modified form of tRNAi (Met) is the actual limiting factor. We show that changing the proportion of t(6)A-modified tRNAi (Met), by expression of an un-modifiable tRNAi (Met) or changing the levels of Tcs3, regulate target of rapamycin (TOR) kinase activity and influences cell and animal growth in vivo. These findings reveal an unprecedented relationship between the translation machinery and TOR, where translation efficiency, limited by the availability of t(6)A-modified tRNA, determines growth potential in eukaryotic cells.
authors.affiliation: From the Centro de Regulación del Genoma, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Santiago, Chile 7800024 and.
authors.forename: Diego
authors.initials: D
authors.lastname: Rojas-Benitez
authors.affiliation: the Department of Microbiology and Cell Science, University of Florida, Gainesville, Florida32611-0700.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: Thiaville
authors.affiliation: the Department of Microbiology and Cell Science, University of Florida, Gainesville, Florida32611-0700.
authors.forename: Valérie
authors.identifier: http://orcid.org/0000-0002-9955-3785
authors.initials: V
authors.lastname: de Crécy-Lagard
authors.affiliation: From the Centro de Regulación del Genoma, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Santiago, Chile 7800024 and alglavic@uchile.cl.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Glavic
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics*; D018387:Codon, Initiator / Q000235:genetics; D004330:Drosophila / Q000235:genetics; D005786:Gene Expression Regulation; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D012358:RNA, Transfer, Met / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: D018387:Codon, Initiator; D012358:RNA, Transfer, Met; D029701:Saccharomyces cerevisiae Proteins; C117606:VPS54 protein, S cerevisiae; D033921:Vesicular Transport Proteins; C108301:BUD32 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases
keywords: Drosophila; cell growth; transfer RNA (tRNA); translation; yeast