This project is focused on two components of the translation apparatus that are responsible for the rules of the modern, universal genetic code. The code is established by aminoacylation reactions catalyzed by enzymes known as aminoacyl transfer RNA synthetases. In these reactions, each amino acid is matched with its nucleotide triplet imbedded in the anticodon of the cognate transfer RNA. The enzymes are ancient and appeared at or before the split that gave rise to the three kingdoms of living organisms. Highly specific interactions between the synthetases, their tRNAs, and their amino acids are essential for the accuracy of and maintenance of the code. Standard protein-nucleic acid or protein-small molecule interactions are by themselves not able to sustain the code. Instead, editing reactions that are tRNA-dependent are critical for preventing errors of aminoacylation that would invade, or contaminate, the code. In the proposed work, genetic manipulations explore the consequences of disruption of the editing activity of a specific synthetase. This work includes investigations of the production of statistical proteins, where more than one amino acid can be inserted at a specific codon in an mRNA. Also, with the editing center of a synthetase disabled, the compensatory cellular mechanisms that can be recruited to clear errors of aminoacylation will be studied. These investigations will be extended to study the disruption of editing in mammalian cells and the possible connections to disease. Further work focuses on how nature has developed other mechanisms to preserve the integrity of the code, including the complexities found in eukaryotic cells where mitochondrial and cytoplasmic systems of protein synthesis appear to force changes in the rules for synthetase-tRNA recognition. ? ?
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