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Scripps Laboratories for tRNA Synthetase Research

About SLTSR

The laboratory is focused on aminoacyl tRNA synthetases. The enzymes are ancient and are believed to have appeared in the transition from the putative RNA world to the theatre of proteins. The algorithm of the genetic code is established in the first reaction of protein synthesis. In this reaction, aminoacyl tRNA synthetases catalyze the attachments of amino acids to their cognate transfer RNAs. Errors of translation occur when a mischarged tRNA is released from the synthetase, so that the mischarged amino acid is then inserted at the wrong codon in mRNA. The laboratory investigates synthetases in their role as catalysts of aminoacylation and how that is connected to disease. In addition, the synthetases have resected forms (alternative splice variants and natural proteolytic fragments) and have extracellular and nuclear functions outside of translation. These novel functions are subject to intensive investigations by the laboratory, and may be intimately connected to heritable genetic diseases associated with tRNA synthetases.

Occasional errors of aminoacylation occur naturally and these can result in mistranslation, where the mischarged amino acid is inserted at the wrong codon in mRNA. Over the eons, aminoacyl tRNA synthetases developed powerful mechanisms for correcting errors of aminoacylation. But if these mechanisms are disturbed (for example by mutations that attenuate the error-correcting activities), then errors of translation will occur. Recent work by us and collaborators showed that these errors cause cell and animal pathologies. Much focus is on structure-function relationships for clearance of errors of aminoacylation. We also learned from recent work that mistranslation is mutagenic in aging bacteria. These recent observations raise the question of whether a similar mutagenic response might be seen in aging higher organisms and could be oncogenic and contribute to the higher incidence of oncogenesis seen in aging populations.

Synthetases in mammalian cells are now known to have expanded functions, including activities in signal transduction pathways, such as those for angiogenesis and inflammation. These novel functions often result from the production of resected forms (alternative splice variants or natural fragments produced by proteolysis). Cell surface receptors for secreted forms and interacting partners in the nucleus are being identified and investigated from the standpoint of structure-function relationships, and understanding the evolutionary forces that introduced new motifs and activities in tRNA synthetases. These activities offer the opportunity to understand the mechanistic side of expanded functions to the point where therapeutic applications can be envisioned.

For all of this work, a cross-disciplinary approach is used. Methods and logic of biochemistry and molecular and cell biology are merged with genetics, x-ray crystallography, and evolutionary analysis.

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