Aminoacyl-tRNA synthetases (AARSs) are a group of essential and ubiquitous "house-keeping" enzymes responsible for charging corresponding amino acids to their cognate transfer RNAs (tRNAs) and providing the correct substrates for high-fidelity protein synthesis. During the last three decades, wide-ranging biochemical and genetic studies have revealed non-catalytic regulatory functions of multiple AARSs in biological processes including gene transcription, mRNA translation, and mitochondrial RNA splicing, and in diverse species from bacteria through yeasts to vertebrates. Remarkably, ongoing exploration of non-canonical functions of AARSs has shown that they contribute importantly to control of inflammation, angiogenesis, immune response, and tumorigenesis, among other critical physiopathological processes. In this chapter we consider the non-canonical functions of AARSs in regulating gene expression by mechanisms not directly related to their enzymatic activities, namely, at the levels of mRNA production, processing, and translation. The scope of AARS-mediated gene regulation ranges from negative autoregulation of single AARS genes to gene-selective control, and ultimately to global gene regulation. Clearly, AARSs have evolved these auxiliary regulatory functions that optimize the survival and well-being of the organism, possibly with more complex regulatory mechanisms associated with more complex organisms. In the first section on transcriptional control, we introduce the roles of autoregulation by Escherichia coli AlaRS, transcriptional activation by human LysRS, and transcriptional inhibition by vertebrate SerRS. In the second section on translational control, we recapitulate the roles of GluProRS in translation repression at the initiation step, auto-inhibition of E. coli thrS mRNA translation by ThrRS, and global translational arrest by phosphorylated human MetRS. Finally, in the third section, we describe the RNA splicing activities of mitochondrial TyrRS and LeuRS in Neurospora and yeasts, respectively.
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