Defining the Role of Aminoacyl-tRNA Synthetases in Human Health and Disease

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

PROJECT ABSTRACT Aminoacyl-tRNA synthetases (ARSs) are a ubiquitously expressed, essential class of enzymes responsible for ligating amino acids to cognate tRNA molecules. Importantly, all 37 loci encoding an ARS have been implicated in dominant and/or recessive clinical phenotypes, making these enzymes a major contributor to human inherited disease. It is now important to systematically assess the role of ARS alleles in human disease phenotypes and to determine how they affect gene function and cellular homeostasis. These data will provide insight into the molecular pathology of disease-associated ARS alleles, which affect a wide range of tissues. Furthermore, defining the molecular mechanisms of ARS-associated diseases will allow rapid patient diagnosis through distinguishing pathogenic from non-pathogenic alleles in human populations. We and others have shown that disease-associated ARS alleles cause a loss-of-function effect on tRNA charging. However, the goals for the next five years are to address a number of critical, unanswered questions, including: (1) What is the full complement of pathogenic ARS alleles in dominant and recessive disease? (2) What distinguishes pathogenic versus non-pathogenic ARS variants? (3) How are ARS loci regulated? and (4) What is the complete repertoire of ARS functions in mammalian cells? Here, we employ multiple established and complementary model systems—computational, biochemical, cellular, yeast, worm, and mouse—to address the above questions. Combined, the areas of study outlined in this proposal will improve our understanding of ARS biology and allow us to define how certain ARS alleles give rise to dominant and/or recessive human diseases. Furthermore, the breadth of the proposed studies—including both foundational and applied basic science—will facilitate the professional development of laboratory members, and will result in a sustainable research program.