Studies on Transfer RNA

Yale University, New Haven CT

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Abstract

DESCRIPTION (provided by applicant) Aminoacyl-tRNAs provide the interface between genetic information encoded in the DMA 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, a 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 routes of aminoacyl-tRNA synthesis: (i) Cysteinyl-tRNA synthesis in methanogenic archaea by a still unknown enzyme/process, (ii) Pyrrolysyl-tRNA synthesis by an aminoacyl-tRNA synthetase-like uncharacterized enzyme, (iii) Asparaginyl-tRNA synthesis and glutaminyl-tRNA synthesis by the three kingdom-specific tRNA-dependent amidotransferases. As a natural complement to these investigations, studies on quality control in protein synthesis will be performed at several levels: (i) tRNA maturation in archaea from tRNA genes encoding half-molecules, (ii) In vivo editing by class II aminoacyl-tRNA synthetases. (iii) Protein quality when mischarged tRNA is present in the cell. 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 novel aspects of aminoacyl-tRNA formation will be invaluable for ongoing efforts to develop anti-infective drugs targeted against aminoacyl-tRNA synthesis.