title: Trm9-Catalyzed tRNA Modifications Regulate Global Protein Expression by Codon-Biased Translation.
abstract: Post-transcriptional modifications of transfer RNAs (tRNAs) have long been recognized to play crucial roles in regulating the rate and fidelity of translation. However, the extent to which they determine global protein production remains poorly understood. Here we use quantitative proteomics to show a direct link between wobble uridine 5-methoxycarbonylmethyl (mcm5) and 5-methoxy-carbonyl-methyl-2-thio (mcm5s2) modifications catalyzed by tRNA methyltransferase 9 (Trm9) in tRNAArg(UCU) and tRNAGlu(UUC) and selective translation of proteins from genes enriched with their cognate codons. Controlling for bias in protein expression and alternations in mRNA expression, we find that loss of Trm9 selectively impairs expression of proteins from genes enriched with AGA and GAA codons under both normal and stress conditions. Moreover, we show that AGA and GAA codons occur with high frequency in clusters along the transcripts, which may play a role in modulating translation. Consistent with these results, proteins subject to enhanced ribosome pausing in yeast lacking mcm5U and mcm5s2U are more likely to be down-regulated and contain a larger number of AGA/GAA clusters. Together, these results suggest that Trm9-catalyzed tRNA modifications play a significant role in regulating protein expression within the cell.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Deng
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: I Ramesh
authors.initials: IR
authors.lastname: Babu
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Dan
authors.initials: D
authors.lastname: Su
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Shanye
authors.initials: S
authors.lastname: Yin
authors.affiliation: SUNY College of Nanoscale Science and Engineering, Albany, New York, United States of America.|RNA Institute and Cancer Research Center, University at Albany, State University of New York, Albany, New York, United States of America.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Begley
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.|Singapore-MIT Alliance for Research and Technology, Singapore.
authors.forename: Peter C
authors.initials: PC
authors.lastname: Dedon
mesh_terms: D003062:Codon / Q000235:genetics*; D015966:Gene Expression Regulation, Fungal; D011499:Protein Processing, Post-Translational / Q000235:genetics; D040901:Proteomics; D012343:RNA, Transfer / Q000235:genetics* / Q000378:metabolism; D012270:Ribosomes / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis* / Q000235:genetics; D014529:Uridine / Q000235:genetics; D012359:tRNA Methyltransferases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D003062:Codon; D029701:Saccharomyces cerevisiae Proteins; D012343:RNA, Transfer; C480488:TRM9 protein, S cerevisiae; D012359:tRNA Methyltransferases; D014529:Uridine