Abstract
Aminoacyl-tRNA synthetases (aaRSs) are key enzymes in the mRNA translation machinery, yet they possess numerous non-canonical functions developed during the evolution of complex organisms. The aaRSs and aaRS-interacting multi-functional proteins (AIMPs) are continually being implicated in tumorigenesis, but these connections are often limited in scope, focusing on specific aaRSs in distinct cancer subtypes. Here, we analyze publicly available genomic and transcriptomic data on human cytoplasmic and mitochondrial aaRSs across many cancer types. As high-throughput technologies have improved exponentially, large-scale projects have systematically quantified genetic alteration and expression from thousands of cancer patient samples. One such project is the Cancer Genome Atlas (TCGA), which processed over 20,000 primary cancer and matched normal samples from 33 cancer types. The wealth of knowledge provided from this undertaking has streamlined the identification of cancer drivers and suppressors. We examined aaRS expression data produced by the TCGA project and combined this with patient survival data to recognize trends in aaRSs’ impact on cancer both molecularly and prognostically. We further compared these trends to an established tumor suppressor and a proto-oncogene. We observed apparent upregulation of many tRNA synthetase genes with aggressive cancer types, yet, at the individual gene level, some aaRSs resemble a tumor suppressor while others show similarities to an oncogene. This study provides an unbiased, overarching perspective on the relationship of aaRSs with cancers and identifies certain aaRS family members as promising therapeutic targets or potential leads for developing biological therapy for cancer.
Highlights
Aminoacyl-tRNA synthetases have emerged as multifaceted proteins with complex connections to human disease, including cancer [1,2]
Copy number variations (CNVs) refer to changes in the number of copies of a genetic region caused by deletion or duplication events in the genome
Primarily using the analysis tools cBioPortal, GEPIA2, and the public database generated by the the Cancer Genome Atlas (TCGA) project, we provide a comprehensive and unbiased study of aaRSs in cancer
Summary
Aminoacyl-tRNA synthetases (aaRSs) have emerged as multifaceted proteins with complex connections to human disease, including cancer [1,2]. Genes 2020, 11, 1384 in mRNA translation This activity has been conserved for as long as proteins have existed, and as organisms evolved complex biological systems, such as the immune system and vasculature, the aaRSs correspondingly evolved with them to enable functionality beyond aminoacylation to coordinate and communicate in multi-cellular and multi-system environments [3]. The functional expansion of aaRSs during evolution coincides with sequentially appended domains that supplement the conserved catalytic core, which usually consists of a catalytic domain and a tRNA recognition domain. These additional domains enable unique localizations and/or interactions with binding partners inside (cytosol and nucleus) and outside the cell [4]. The MSC is theorized to have two main purposes: to facilitate protein synthesis by funneling charged tRNAs to the ribosome [7] and to act as a reservoir for the MSC-bound aaRSs to regulate their non-translational activities, such as transcriptional regulation and cell–cell signaling [8]
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