Abstract
Living organisms respond to environmental changes and xenobiotic exposures by regulating gene expression. While heat shock, unfolded protein, and DNA damage stress responses are well-studied at the levels of the transcriptome and proteome, tRNA-mediated mechanisms are only recently emerging as important modulators of cellular stress responses. Regulation of the stress response by tRNA shows a high functional diversity, ranging from the control of tRNA maturation and translation initiation, to translational enhancement through modification-mediated codon-biased translation of mRNAs encoding stress response proteins, and translational repression by stress-induced tRNA fragments. tRNAs need to be heavily modified post-transcriptionally for full activity, and it is becoming increasingly clear that many aspects of tRNA metabolism and function are regulated through the dynamic introduction and removal of modifications. This review will discuss the many ways that nucleoside modifications confer high functional diversity to tRNAs, with a focus on tRNA modification-mediated regulation of the eukaryotic response to environmental stress and toxicant exposures. Additionally, the potential applications of tRNA modification biology in the development of early biomarkers of pathology will be highlighted.
Highlights
In an ever-changing environment, living systems are subjected to stresses such as temperature fluctuations, nutrient limitations, and exposures that damage intracellular biomolecules
The limited availability of extracellular amino acids during starvation leads to the accumulation of uncharged cytosolic transfer RNA (tRNA) that directly bind to the protein kinase GCN2 [20,21]
Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) [8,36,37]. These decreased tRNA modification has been directly linked to the mitochondrial diseases myoclonus diseases are caused by a mutation in mitochondrial tRNA genes, with the change in sequence epilepsy associated with ragged-red fibers (MERRF) and mitochondrial encephalopathy, lactic acidosis, preventing formation of the tRNA modifications s2 and 5-taurinomethyluridine, both and stroke-like episodes (MELAS) [8,36,37]
Summary
In an ever-changing environment, living systems are subjected to stresses such as temperature fluctuations, nutrient limitations, and exposures that damage intracellular biomolecules. We focus on recently emerging mechanisms of cellular stress response involving the dynamic regulation of ribonucleoside modifications that control transfer RNA (tRNA) metabolism, structure, and function, which, in turn, modulate protein translation and a cell’s ability to cope with stress. Beyond their role as adaptors in protein synthesis, tRNAs have been shown to be critically involved in many other cellular processes. The limited availability of extracellular amino acids during starvation leads to the accumulation of uncharged cytosolic tRNAs that directly bind to the protein kinase GCN2 [20,21] This tRNA binding activates the GCN2 kinase activity and results in the phosphorylation of elF2, which in turn regulates translation in amino acid-starved cells and promotes increased synthesis of the transcription factor GCN4 that activates amino acid biosynthetic genes. We explore how tRNA modifications play a role in this tRNA-based regulation of cellular processes in the face of stressful conditions
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