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

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 m3C 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.