Studies On Transfer RNA

Yale University, New Haven CT

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Abstract

DESCRIPTION (Applicant's abstract): Aminoacyl-tRNAs provide the interface between genetic information encoded in the nucleotide sequence of a gene and the amino acid sequence of the corresponding protein. The synthesis of correctly aminoacylated tRNAs is generally held to be the sole preserve of the aminoacyl-tRNA synthetases, ubiquitous and ancient family of enzymes found throughout the living kingdom. Despite the essential function of this enzyme family, the vast majority of organisms have been found to lack at least one canonical aminoacyl-tRNA synthetase with some lacking up to four. In such cases, the corresponding aminoacyl-tRNA is instead synthesized by either a non-canonical aminoacyl-tRNA synthetase or by an alternative pathway. This application is primarily directed towards investigating the following alternative five routes of aminoacyl-tRNA synthesis: (1) Cys-tRNA and Pro-tRNA synthesis by the dual specificity prolyl-cysteinyl-tRNA synthetase. (ii) Lys-tRNA synthesis by the class I lysyl-tRNA synthetase. (iii) Asn-tRNA synthesis and Gln-tRNA synthesis by the three kingdom-specific tRNA-dependent amidotransferases. As a natural complement to these studies, global analyses of both canonical and non canonical aminoacyl-tRNA synthesis will be undertaken based upon recent developments in the field of functional genomics to gain a broader insight into these processes. The overall objective of this study is to provide a detailed and integrated description of the process of aminoacyl-tRNA synthesis and its myriad roles in extant organisms. Such information will provide key insights into the origins and evolution of contemporary mRNA-encoded protein synthesis. On a prosaic but no less important level, the availability of in-depth knowledge on the more novel aspects of aminoacyl-tRNA formation will be invaluable for ongoing efforts to develop anti-infective drugs targeted against aminoacyl-tRNA synthesis.