Highly Predictive Reprogramming of tRNA Modifications Is Linked to Selective Expression of Codon-Biased Genes

Chem Res Toxicol. 2015 May 18;28(5):978-88. doi: 10.1021/acs.chemrestox.5b00004. Epub 2015 Apr 13.


Cells respond to stress by controlling gene expression at several levels, with little known about the role of translation. Here, we demonstrate a coordinated translational stress response system involving stress-specific reprogramming of tRNA wobble modifications that leads to selective translation of codon-biased mRNAs representing different classes of critical response proteins. In budding yeast exposed to four oxidants and five alkylating agents, tRNA modification patterns accurately distinguished among chemically similar stressors, with 14 modified ribonucleosides forming the basis for a data-driven model that predicts toxicant chemistry with >80% sensitivity and specificity. tRNA modification subpatterns also distinguish SN1 from SN2 alkylating agents, with SN2-induced increases in m(3)C in tRNA mechanistically linked to selective translation of threonine-rich membrane proteins from genes enriched with ACC and ACT degenerate codons for threonine. These results establish tRNA modifications as predictive biomarkers of exposure and illustrate a novel regulatory mechanism for translational control of cell stress response.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylating Agents / toxicity*
  • Codon / genetics*
  • Oxidants / toxicity*
  • Protein Biosynthesis / drug effects*
  • RNA, Fungal / genetics
  • RNA, Transfer / genetics*
  • Saccharomycetales / drug effects*
  • Saccharomycetales / genetics


  • Alkylating Agents
  • Codon
  • Oxidants
  • RNA, Fungal
  • RNA, Transfer