The emerging role of complex modifications of tRNA(Lys)(UUU) in signaling pathways

Coordination of cell growth with nutrient availability, in particular amino acids, is a central problem that has been solved by the implementation of complex regulatory cascades. Although the specific regulatory mechanisms differ between kingdoms and species, a common theme is the use of tRNA molecules as sensors and transducers of amino acid starvation. In many bacteria, amino acid starvation leads to high levels of uncharged tRNAs, a signal for the synthesis of the stringent response’s alarmones, halting transcription of stable RNAs and inducing the synthesis of amino acid synthesis pathways 1. In gram-positive Bacteria (as well as the Deinococcus-Thermus clade), uncharged tRNAs bind structures (T-boxes) in the leader sequences of mRNA encoding gene, activating the expression of genes involved in amino acid metabolism 2. In eukaryotes, the conserved General Amino Acid Control (GAAC) response is triggered by shortage of amino acids that leads to the binding of uncharged tRNAs to Gcn2 kinase and, through a cascade of events, to the activation of the central activator of amino acid synthesis genes, Gcn4 3. As the study by Scheidt et al. 4 and several other recent studies in this field reveal, variations in charging levels are not the only mechanism by which tRNAs play a role in amino acid starvation responses; levels of post-transcriptional modifications also seem to play major roles.