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J. Biol. Chem., Vol. 277, Issue 48, 45729-45733, November 29, 2002

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Genetic Code Ambiguity
CELL VIABILITY RELATED TO SEVERITY OF EDITING DEFECTS IN MUTANT tRNA SYNTHETASES^*

Leslie A. Nangle, Valérie de Crécy Lagard, Volker Döring^§, and Paul Schimmel^¶

From the  Departments of Molecular Biology and Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037 and ^§ Evologic SA, 4 rue Pierre Fontaine, 91000 Evry, France

The rules of the genetic code are established in reactions that aminoacylate tRNAs with specific amino acids. Ambiguity in the code is prevented by editing activities whereby incorrect aminoacylations are cleared by specialized hydrolytic reactions of aminoacyl tRNA synthetases. Whereas editing reactions have long been known, their significance for cell viability is still poorly understood. Here we investigated in vitro and in vivo four different mutations in the center for editing that diminish the proofreading activity of valyl-tRNA synthetase (ValRS). The four mutant enzymes were shown to differ quantitatively in the severity of the defect in their ability to clear mischarged tRNA in vitro. Strikingly, in the presence of excess concentrations of -aminobutyrate, one of the amino acids that is misactivated by ValRS, growth of bacterial strains bearing these mutant alleles is arrested. The concentration of misactivated amino acid required for growth arrest correlates inversely in a rank order with the degree of the editing defect seen in vitro. Thus, cell viability depends directly on the suppression of genetic code ambiguity by these specific editing reactions and is finely tuned to any perturbation of these reactions.

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