Journal
RNA BIOLOGY
Volume 9, Issue 7, Pages 990-1001Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/rna.20531
Keywords
Trm9; translation infidelity; codon; protein stress; unfolded protein response; heat shock response; wobble base; tRNA; modification
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Funding
- National Institute of Environmental Health Sciences [R01 ES015037, R01 ES017010, P30 ES002109]
- MIT Westaway Fund
- Singapore-MIT Alliance for Research and Technology
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Correct codon-anticodon pairing promotes translational fidelity, with these interactions greatly facilitated by modified nucleosides found in tRNA. We hypothesized that wobble uridine modifications catalyzed by tRNA methyltransferase 9 (Trm9) are essential for translational fidelity. In support, we have used phenotypic, reporter and protein-based assays to demonstrate increased translational infidelity in trm9 Delta Saccharomyces cerevisiae cells. Codon reengineering studies suggest that Trm9-catalyzed tRNA modifications promote fidelity during the translation of specific genes, those rich in arginine and glutamic acid codons from mixed boxes. Using quantitative tRNA modification analysis, we determined that trm9 Delta cells are only deficient in 2 of 23 tRNA modifications, with those 2, 5-methoxycarbonylmethyluridine (mcm(5)U) and 5-methoxycarbonylmethyl-2-thiouridine (mcm(5)s(2)U), classified as key determinants of translational fidelity. We also show that in the absence of mcm(5)U and mcm(5)s(2)U, the resulting translational infidelity promotes protein errors and activation of unfolded protein and heat shock responses. These data support a model in which Trm9-catalyzed tRNA modifications promote fidelity during the translation of specific transcripts, with decreased wobble base modification leading to translational infidelity, protein errors and activation of protein stress response pathways.
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