Abstract
Histidyl tRNA Synthetase (HARS) is a member of the aminoacyl tRNA synthetase (ARS) family of enzymes. This family of 20 enzymes is responsible for attaching specific amino acids to their cognate tRNA molecules, a critical step in protein synthesis. However, recent work highlighting a growing number of associations between ARS genes and diverse human diseases raises the possibility of new and unexpected functions in this ancient enzyme family. For example, mutations in HARS have been linked to two different neurological disorders, Usher Syndrome Type IIIB and Charcot Marie Tooth peripheral neuropathy. These connections raise the possibility of previously undiscovered roles for HARS in metazoan development, with alterations in these functions leading to complex diseases. In an attempt to establish Danio rerio as a model for studying HARS functions in human disease, we characterized the Danio rerio hars gene and compared it to that of human HARS. Using a combination of bioinformatics, molecular biology, and cellular approaches, we found that while the human genome encodes separate genes for cytoplasmic and mitochondrial HARS protein, the Danio rerio genome encodes a single hars gene which undergoes alternative splicing to produce the respective cytoplasmic and mitochondrial versions of Hars. Nevertheless, while the HARS genes of humans and Danio differ significantly at the genomic level, we found that they are still highly conserved at the amino acid level, underscoring the potential utility of Danio rerio as a model organism for investigating HARS function and its link to human diseases in vivo.
Highlights
Aminoacyl tRNA synthetases (ARS) comprise a family of enzymes responsible for attaching amino acids to their appropriate tRNA molecules, an early step in protein synthesis [1]
In order to meet the universal demand for efficient protein synthesis, eukaryotic organisms require a complete set of aminoacyl tRNA synthetases for each compartment where translation occurs
Over the course of their evolution, aminoacyl-tRNA synthetases have accumulated a number of auxiliary domains, many of which are connected to their various non-canonical functions [40]
Summary
Aminoacyl tRNA synthetases (ARS) comprise a family of enzymes responsible for attaching amino acids to their appropriate tRNA molecules, an early step in protein synthesis [1]. Zebrafish cytoplasmic and mitochondrial HARS are encoded by a single gene modulation, and signal transduction [5,6,7,8]. These additional functions of aminoacyl tRNA synthetases may help explain the growing number of diseases associated with this family of enzymes [9, 10]. The connection between these ubiquitous, essential proteins and the variety of disorders resulting from their deficiency is unclear and indicates a need for further investigation into the many roles of aminoacyl tRNA synthetases
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