Genomic organization, transcriptional mapping, and evolutionary implications of the human bi-directional histidyl-tRNA synthetase locus (HARS/HARSL)

Abstract

Histidyl-tRNA synthetase catalyses the covalent ligation of histidine to its cognate tRNA as an early step in protein biosynthesis. In humans, the histidyl-tRNA synthetase gene (HARS) is oriented opposite of a synthetase-like gene (HARSL) that bears striking homology to HARS. In this report, we describe the genomic organization of the HARS/HARSL locus and map multiple transcripts originating from a bi-directional promoter controlling the differential expression of these genes. The HARS and HARSL genes each contain 13 exons with strong structural and sequence homology over exons 3-12. HARS transcripts originate from two distinct promoters; a cluster of short transcripts map 15-65 bp upstream of the HARS ORF while a single, longer transcript (352 bp 5 0 -UTR) maps to a distal promoter. Similarly, multiple HARSL transcripts (mapping 10-198 bp upstream of its ORF) are produced by the shared bi-directional promoter. Human and rodent HARS/HARSL loci are homologous and support a model of inverted gene duplication to explain the emergence of HARSL during mammalian evolution. Ó

Nucleic acid-associated autoantigens: Pathogenic involvement and therapeutic potential

“…HARS2, a mitochondrial version of HARS, shares 72% amino acididentity with HARS [314]. Similarly, there are mitochondrial forms of other aaRSs [315].…”

“…The catalytic domains of all the aaRSs of a given class are found to be highly homologous, while class I and class II aaRSs are unrelated to one another. Pufferfish and human HARS share 84% aa identity, demonstrating a high degree of conservation across species [314].…”

Crystal Structures of Trypanosomal Histidyl-tRNA Synthetase Illuminate Differences between Eukaryotic and Prokaryotic Homologs

“…There are two mammalian HisRS genes, HARS and HARS2 (also known as HARSL), which arose by inverted gene duplication16,17. The human HisRS gene products are 79% sequence identical to each other outside of the WHEP domain.…”

The role of jo-1 in the immunopathogenesis of polymyositis: Current hypotheses

“…Some variation in the expression of Jo-1 (as well as the Jo-1 homologue HARSL that likely arose from an inverted gene duplication event through intron 1 of histidyl-transfer RNA synthetase) is likely caused by tissue-specific regulation of gene transcription from a complex, bidirectional promoter [34]. Conceptually, however, the most tenable explanation is that in PM, antigens such as Jo-1 are abnormally exposed to the immune system in a tissue-specific manner.…”