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Aminoacyl‐tRNA synthetases (aaRSs) are essential enzymes to support protein synthesis in all organisms. Recent studies, empowered by advancements in genome sequencing, have uncovered an increasing number of disease‐causing mutations in aaRSs. Monoallelic aaRS mutations typically lead to dominant peripheral neuropathies such as Charcot–Marie–Tooth (CMT) disease, whereas biallelic aaRS mutations often impair the central nervous system (CNS) and cause neurodevelopmental disorders. Here, we review recent progress in the disease onsets, molecular basis, and potential therapies for diseases caused by aaRS mutations, with a focus on biallelic mutations in cytoplasmic aaRSs. [ABSTRACT FROM AUTHOR]

Human mitochondrial tRNA (hmt-tRNA) mutations are associated with a variety of diseases including mitochondrial myopathies, diabetes, encephalopathies, and deafness. Because the current understanding of the precise molecular mechanisms of these mutations is limited, there is no efficient method to treat their associated mitochondrial diseases. Here, we use a variety of known mutations in hmt-[tRNA.sup.Phe] to investigate the mechanisms that lead to malfunctions. We tested the impact of hmt-[tRNA.sup.Phe] mutations on aminoacylation, structure, and translation elongation-factor binding. The majority of the mutants were pleiotropic, exhibiting defects in aminoacylation, global structure, and elongation-factor binding. One notable exception was the G34A anticodon mutation of hmt-[tRNA.sup.Phe] (mitochondrial DNA mutation G611A), which is associated with MERRF (myoclonic epilepsy with ragged red fibers). In vitro, the G34A mutation decreases aminoacylation activity by 100-fold, but does not affect global folding or recognition by elongation factor. Furthermore, G34A hmt-[tRNA.sup.Phe] does not undergo adenosine-to-inosine (A-to-I) editing, ruling out miscoding as a possible mechanism for mitochondrial malfunction. To improve the aminoacylation state of the mutant tRNA, we modified the tRNA binding domain of the nucleus-encoded human mitochondrial phenylalanyl-tRNA synthetase, which aminoacylates hmt-[tRNA.sup.Phe] with cognate phenylalanine. This variant enzyme displayed significantly improved aminoacylation efficiency for the G34A mutant, suggesting a general strategy to treat certain classes of mitochondrial diseases by modification of the corresponding nuclear gene. aminoacyl-tRNA synthetase | translation | mitochondria

The misincorporation of an incorrect amino acid into a polypeptide during protein synthesis is considered a detrimental phenomenon. A mistranslated protein is often misfolded and degraded or nonfunctional and results in an increased cost to quality control machinery. Despite these costs, errors during protein synthesis are common in bacteria. Here, we report that mistranslation in Escherichia coli increase the protein level of the heat shock sigma factor RpoH and protect cells against heat stress. Surprisingly, this increase in RpoH due to mistranslation is dependent on the presence of the general stress response sigma factor RpoS. This report provides evidence for a protective function of mistranslation and suggests a novel regulatory role of RpoS in the heat shock response. [ABSTRACT FROM AUTHOR]