Cells respond to environmental stressors and xenobiotic exposures
using regulatory networks to control gene expression, and there is an emerging
appreciation for the role of numerous postsynthetic chemical modifications of
DNA, RNA, and proteins in controlling transcription and translation of the stress
response. In this Perspective, we present a model for a new network that regulates
the cellular response to xenobiotic exposures and other stresses in which stressinduced
reprogramming of a system of dozens of post-transcriptional modifications
on tRNA (tRNA) promotes selective translation of codon-biased mRNAs for
critical response proteins. As a product of novel genomic and bioanalytical
technologies, this model has strong parallels with the regulatory networks of DNA
methylation in epigenetics and the variety of protein secondary modifications comprising signaling pathways and the histone
code. When present at the tRNA wobble position, the modified ribonucleosides enhance the translation of mRNAs in which the
cognate codons of the tRNAs are highly over-represented and that represent critical stress response proteins. A parallel system
may also downregulate the translation of families of proteins. Notably, dysregulation of the tRNA methyltransferase enzymes in
humans has also been implicated in cancer etiology, with demonstrated oncogenic and tumor-suppressive effects.