Dominant-negative NARS1 R534* mutation causes wild-type subunit poisoning and heterodimer predominance in cells.

Aminoacyl-tRNA synthetases (aaRSs) catalyze the aminoacylation of tRNA with their cognate amino acids, an essential step in protein biosynthesis. While biallelic mutations in aaRSs often result in severe multi-organ dysfunction accompanied by developmental delays, monoallelic mutations typically cause milder, tissue-specific symptoms. However, a de novo monoallelic nonsense mutation (R534*) in the asparaginyl-tRNA synthetase (AsnRS)-resulting in a premature stop codon and 15-residue C-terminal truncation-has been identified in multiple families and is associated with severe neurodevelopmental symptoms.

Purification and validation of asparaginyl-tRNA synthetase heterodimer with indistinguishable subunits.

Oligomerization can influence the stability and activity of a protein. The majority of enzymes, including aminoacyl-tRNA synthetases, become catalytically active upon forming homodimers. Residues located at the dimerization interface are highly conserved and mutations arising within can cause severe disease phenotypes.

Domain collapse and active site ablation generate a widespread animal mitochondrial seryl-tRNA synthetase.

Through their aminoacylation reactions, aminoacyl tRNA-synthetases (aaRS) establish the rules of the genetic code throughout all of nature. During their long evolution in eukaryotes, additional domains and splice variants were added to what is commonly a homodimeric or monomeric structure. These changes confer orthogonal functions in cellular activities that have recently been uncovered.

Phosphorylation of seryl-tRNA synthetase by ATM/ATR is essential for hypoxia-induced angiogenesis.

Hypoxia-induced angiogenesis maintains tissue oxygen supply and protects against ischemia but also enhances tumor progression and malignancy. This is mediated through activation of transcription factors like hypoxia-inducible factor 1 (HIF-1) and c-Myc, yet the impact of hypoxia on negative regulators of angiogenesis is unknown. During vascular development, seryl-tRNA synthetase (SerRS) regulates angiogenesis through a novel mechanism by counteracting c-Myc and transcriptionally repressing vascular endothelial growth factor A (VEGFA) expression.

Multi-Omics Database Analysis of Aminoacyl-tRNA Synthetases in Cancer.

Aminoacyl-tRNA synthetases (aaRSs) are key enzymes in the mRNA translation machinery, yet they possess numerous non-canonical functions developed during the evolution of complex organisms. The aaRSs and aaRS-interacting multi-functional proteins (AIMPs) are continually being implicated in tumorigenesis, but these connections are often limited in scope, focusing on specific aaRSs in distinct cancer subtypes. Here, we analyze publicly available genomic and transcriptomic data on human cytoplasmic and mitochondrial aaRSs across many cancer types.