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Emerging Roles of tRNAs in Health and Disease
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Emerging Roles of tRNAs in Health and Disease

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "RNA".

Deadline for manuscript submissions: closed (20 February 2024) | Viewed by 16657

Special Issue Editors

Prof. Dr. Martin Holcik

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Guest Editor
Department of Health Sciences, Carleton University, Ottawa, ON K1S 5B6, Canada
Interests: mRNA translation; tRNA; mitochondrial disease; cell death; signaling
Special Issues, Collections and Topics in MDPI journals
Angelo Slade

E-Mail
Guest Editor Assistant
Department of Health Sciences, Carleton University, Ottawa, ON K1S 5B6, Canada
Interests: mRNA translation; tRNA modification; genetic disease; mitochondrial disease

Special Issue Information

Dear Colleagues,

Since the original discovery of tRNA in 1958, tremendous progress has been made in our understanding of the biological role of this fascinating molecule, with much attention being garnered in recent years. tRNA is no longer viewed as just an ‘adaptor’ molecule that mediates the translation of the genetic information from nucleic acid to protein. tRNAs are heavily modified, processed, and even cleaved to fulfill diverse roles in the cell, ranging from RNA processing to cell proliferation to DNA damage modulation to translation to signaling and cellular stress responses. Inappropriate or uncoordinated modifications and processing of tRNAs, along with many mutations in tRNA genes, both nuclear and mitochondrial, are increasingly associated with various cellular conditions and human pathologies. Additionally, mutations within certain protein coding genes resulting in a changed codon bias have been implicated in attributing to disease states, often exacerbated by tissue-specific tRNA expression. Not surprisingly, tRNA fragments are being explored as new biomarkers of disease diagnosis and progression.

This Special Issue, “Emerging Roles of tRNAs in Health and Disease”, will examine the role of tRNA in health and disease. We invite you to submit review articles, original papers, and short communications on the broad topic of tRNA biology and the processes, conditions, and pathologies caused by or associated with disturbances in proper tRNA biology or due to mutations in tRNA genes. We hope that this Special Issue will be a valuable compendium of the current knowledge of tRNA structure and function as it is linked to human disease.

Prof. Dr. Martin Holcik
Guest Editor
Angelo Slade 
Guest Editor Assistant

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • transfer RNA
  • tRFs
  • tRNA-derived fragments
  • tsRNAs
  • tRNA processing
  • tRNA modifications
  • tiRNA
  • mitochondrial tRNA
  • disease

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Published Papers (5 papers)

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Research

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14 pages, 1853 KiB  
Article
TRNT-1 Deficiency Is Associated with Loss of tRNA Integrity and Imbalance of Distinct Proteins
by Thet Fatica, Turaya Naas, Urszula Liwak, Hannah Slaa, Maryam Souaid, Brianna Frangione, Ribal Kattini, Antoine Gaudreau-Lapierre, Laura Trinkle-Mulcahy, Pranesh Chakraborty and Martin Holcik
Genes 2023, 14(5), 1043; https://doi.org/10.3390/genes14051043 - 5 May 2023
Viewed by 2927
Abstract
Mitochondrial diseases are a group of heterogeneous disorders caused by dysfunctional mitochondria. Interestingly, a large proportion of mitochondrial diseases are caused by defects in genes associated with tRNA metabolism. We recently discovered that partial loss-of-function mutations in tRNA Nucleotidyl Transferase 1 (TRNT1 [...] Read more.
Mitochondrial diseases are a group of heterogeneous disorders caused by dysfunctional mitochondria. Interestingly, a large proportion of mitochondrial diseases are caused by defects in genes associated with tRNA metabolism. We recently discovered that partial loss-of-function mutations in tRNA Nucleotidyl Transferase 1 (TRNT1), the nuclear gene encoding the CCA-adding enzyme essential for modifying both nuclear and mitochondrial tRNAs, causes a multisystemic and clinically heterogenous disease termed SIFD (sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay; SIFD). However, it is not clear how mutations in a general and essential protein like TRNT1 cause disease with such clinically broad but unique symptomatology and tissue involvement. Using biochemical, cell, and mass spectrometry approaches, we demonstrate that TRNT1 deficiency is associated with sensitivity to oxidative stress, which is due to exacerbated, angiogenin-dependent cleavage of tRNAs. Furthermore, reduced levels of TRNT1 lead to phosphorylation of Eukaryotic Translation Initiation Factor 2 Subunit Alpha (eIF2α), increased reactive oxygen species (ROS) production, and changes in the abundance of distinct proteins. Our data suggest that the observed variable SIFD phenotypes are likely due to dysregulation of tRNA maturation and abundance, which in turn negatively affects the translation of distinct proteins. Full article
(This article belongs to the Special Issue Emerging Roles of tRNAs in Health and Disease)
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20 pages, 2842 KiB  
Article
Genetic Interaction of tRNA-Dependent Mistranslation with Fused in Sarcoma Protein Aggregates
by Jeremy T. Lant, Farah Hasan, Julia Briggs, Ilka U. Heinemann and Patrick O’Donoghue
Genes 2023, 14(2), 518; https://doi.org/10.3390/genes14020518 - 18 Feb 2023
Cited by 4 | Viewed by 2837
Abstract
High-fidelity protein synthesis requires properly aminoacylated transfer RNAs (tRNAs), yet diverse cell types, from bacteria to humans, show a surprising ability to tolerate errors in translation resulting from mutations in tRNAs, aminoacyl-tRNA synthetases, and other components of protein synthesis. Recently, we characterized a [...] Read more.
High-fidelity protein synthesis requires properly aminoacylated transfer RNAs (tRNAs), yet diverse cell types, from bacteria to humans, show a surprising ability to tolerate errors in translation resulting from mutations in tRNAs, aminoacyl-tRNA synthetases, and other components of protein synthesis. Recently, we characterized a tRNASerAGA G35A mutant (tRNASerAAA) that occurs in 2% of the human population. The mutant tRNA decodes phenylalanine codons with serine, inhibits protein synthesis, and is defective in protein and aggregate degradation. Here, we used cell culture models to test our hypothesis that tRNA-dependent mistranslation will exacerbate toxicity caused by amyotrophic lateral sclerosis (ALS)-associated protein aggregation. Relative to wild-type tRNA, we found cells expressing tRNASerAAA showed slower but effective aggregation of the fused in sarcoma (FUS) protein. Despite reduced levels in mistranslating cells, wild-type FUS aggregates showed similar toxicity in mistranslating cells and normal cells. The aggregation kinetics of the ALS-causative FUS R521C variant were distinct and more toxic in mistranslating cells, where rapid FUS aggregation caused cells to rupture. We observed synthetic toxicity in neuroblastoma cells co-expressing the mistranslating tRNA mutant and the ALS-causative FUS R521C variant. Our data demonstrate that a naturally occurring human tRNA variant enhances cellular toxicity associated with a known causative allele for neurodegenerative disease. Full article
(This article belongs to the Special Issue Emerging Roles of tRNAs in Health and Disease)
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15 pages, 4889 KiB  
Article
ThrRS-Mediated Translation Regulation of the RNA Polymerase III Subunit RPC10 Occurs through an Element with Similarity to Cognate tRNA ASL and Affects tRNA Levels
by Ofri Levi, Monalisha Mallik and Yoav S. Arava
Genes 2023, 14(2), 462; https://doi.org/10.3390/genes14020462 - 10 Feb 2023
Cited by 1 | Viewed by 2341
Abstract
Aminoacyl tRNA synthetases (aaRSs) are a well-studied family of enzymes with a canonical role in charging tRNAs with a specific amino acid. These proteins appear to also have non-canonical roles, including post-transcriptional regulation of mRNA expression. Many aaRSs were found to bind mRNAs [...] Read more.
Aminoacyl tRNA synthetases (aaRSs) are a well-studied family of enzymes with a canonical role in charging tRNAs with a specific amino acid. These proteins appear to also have non-canonical roles, including post-transcriptional regulation of mRNA expression. Many aaRSs were found to bind mRNAs and regulate their translation into proteins. However, the mRNA targets, mechanism of interaction, and regulatory consequences of this binding are not fully resolved. Here, we focused on yeast cytosolic threonine tRNA synthetase (ThrRS) to decipher its impact on mRNA binding. Affinity purification of ThrRS with its associated mRNAs followed by transcriptome analysis revealed a preference for mRNAs encoding RNA polymerase subunits. An mRNA that was significantly bound compared to all others was the mRNA encoding RPC10, a small subunit of RNA polymerase III. Structural modeling suggested that this mRNA includes a stem-loop element that is similar to the anti-codon stem loop (ASL) structure of ThrRS cognate tRNA (tRNAThr). We introduced random mutations within this element and found that almost every change from the normal sequence leads to reduced binding by ThrRS. Furthermore, point mutations at six key positions that abolish the predicted ASL-like structure showed a significant decrease in ThrRS binding with a decrease in RPC10 protein levels. Concomitantly, tRNAThr levels were reduced in the mutated strain. These data suggest a novel regulatory mechanism in which cellular tRNA levels are regulated through a mimicking element within an RNA polymerase III subunit in a manner that involves the tRNA cognate aaRS. Full article
(This article belongs to the Special Issue Emerging Roles of tRNAs in Health and Disease)
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Review

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13 pages, 3879 KiB  
Review
Towards a Cure for HARS Disease
by Sarah D. P. Wilhelm, Rosan Kenana, Yi Qiu, Patrick O’Donoghue and Ilka U. Heinemann
Genes 2023, 14(2), 254; https://doi.org/10.3390/genes14020254 - 18 Jan 2023
Cited by 12 | Viewed by 3777
Abstract
Histidyl-tRNA synthetase (HARS) ligates histidine to its cognate transfer RNA (tRNAHis). Mutations in HARS cause the human genetic disorders Usher syndrome type 3B (USH3B) and Charcot-Marie-Tooth syndrome type 2W (CMT2W). Treatment for these diseases remains symptomatic, and no disease specific treatments [...] Read more.
Histidyl-tRNA synthetase (HARS) ligates histidine to its cognate transfer RNA (tRNAHis). Mutations in HARS cause the human genetic disorders Usher syndrome type 3B (USH3B) and Charcot-Marie-Tooth syndrome type 2W (CMT2W). Treatment for these diseases remains symptomatic, and no disease specific treatments are currently available. Mutations in HARS can lead to destabilization of the enzyme, reduced aminoacylation, and decreased histidine incorporation into the proteome. Other mutations lead to a toxic gain-of-function and mistranslation of non-cognate amino acids in response to histidine codons, which can be rescued by histidine supplementation in vitro. We discuss recent advances in characterizing HARS mutations and potential applications of amino acid and tRNA therapy for future gene and allele specific therapy. Full article
(This article belongs to the Special Issue Emerging Roles of tRNAs in Health and Disease)
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16 pages, 1051 KiB  
Review
The Role of Nuclear-Encoded Mitochondrial tRNA Charging Enzymes in Human Inherited Disease
by Christina Del Greco and Anthony Antonellis
Genes 2022, 13(12), 2319; https://doi.org/10.3390/genes13122319 - 9 Dec 2022
Cited by 12 | Viewed by 3581
Abstract
Aminoacyl-tRNA synthetases (ARSs) are highly conserved essential enzymes that charge tRNA with cognate amino acids—the first step of protein synthesis. Of the 37 nuclear-encoded human ARS genes, 17 encode enzymes are exclusively targeted to the mitochondria (mt-ARSs). Mutations in nuclear mt-ARS genes are [...] Read more.
Aminoacyl-tRNA synthetases (ARSs) are highly conserved essential enzymes that charge tRNA with cognate amino acids—the first step of protein synthesis. Of the 37 nuclear-encoded human ARS genes, 17 encode enzymes are exclusively targeted to the mitochondria (mt-ARSs). Mutations in nuclear mt-ARS genes are associated with rare, recessive human diseases with a broad range of clinical phenotypes. While the hypothesized disease mechanism is a loss-of-function effect, there is significant clinical heterogeneity among patients that have mutations in different mt-ARS genes and also among patients that have mutations in the same mt-ARS gene. This observation suggests that additional factors are involved in disease etiology. In this review, we present our current understanding of diseases caused by mutations in the genes encoding mt-ARSs and propose explanations for the observed clinical heterogeneity. Full article
(This article belongs to the Special Issue Emerging Roles of tRNAs in Health and Disease)
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