Book of Abstracts: Albany 2007

category image Albany 2007
Conversation 15
June 19-23 2007

Components and Development of Genetic Code in Relation to Human Disease

Aminoacyl tRNA synthetases establish the genetic code through their aminoacylations of transfer RNAs. These universal, essential enzymes arose early in evolution, presumably taking over the role of ribozymes to establish the code. Sequence relationships between synthetases, together with high resolution x-ray structures of synthetases bound to their cognate transfer RNAs, suggest how the synthetases evolved by gene duplications of two distinct ancestors. During this long evolutionary process, the synthetases developed a powerful activity for preventing mistranslation. This activity stops the wrong amino acid from being inserted at a non-cognate codon. Disruption of this activity causes extreme pathologies in mammalian cells and even a mild defect in editing causes neurodegeneration and ataxia in the mouse. These and other observations link editing defects to the acquisition of mutations in the host organism. As the tree of life developed and expanded into higher eukaryotes, synthetases differentiated further and developed novel functions associated with cytokine signaling pathways and the development of biological systems. In the development of these systems, secretion of a specific tRNA synthetase allowed interaction with extra-cellular receptors that trigger cell signaling events related to angiogenic, inflammatory, and possibly other pathways. Human diseases related to mutations in tRNA synthetases are now widely recognized, and the basis for these disease connections are being worked out and already suggest additional expanded functions for these enzymes. For example, in some initial studies, neurodegenerative conditions that appear in the human population seem not to be related to defects in the aminoacylation or editing functions, but rather suggest a role for synthetases in neurogenesis. Thus, over their long evolution, tRNA synthetases have become an integral part of broad biological systems that extend from translation to cell signaling in higher organisms.

Supported by grants from the National Institutes of Health, the National Foundation for Cancer Research, and the Skaggs Foundation

Paul Schimmel

The Skaggs Institute for Chemical Biology
The Scripps Research Institute
Beckman Center
BCC379,10550 North Torrey Pines Road
La Jolla, CA 92037

Phone: 858-784-8970
Fax: 858-784-8990
Email: schimmel@scripps.edu