Pathways to disease from natural variations in human cytoplasmic tRNAs

Abstract

Edited by Karin Musier-Forsyth Perfectly accurate translation of mRNA into protein is not a prerequisite for life. Resulting from errors in protein synthesis, mistranslation occurs in all cells, including human cells. The human genome encodes >600 tRNA genes, providing both the raw material for genetic variation and a buffer to ensure that resulting translation errors occur at tolerable levels. On the basis of data from the 1000 Genomes Project, we highlight the unanticipated prevalence of mistranslating tRNA variants in the human population and review studies on synthetic and natural tRNA mutations that cause mistranslation or de-regulate protein synthesis. Although mitochondrial tRNA variants are well known to drive human diseases, including developmental disorders, few studies have revealed a role for human cytoplasmic tRNA mutants in disease. In the context of the unexpectedly large number of tRNA variants in the human population, the emerging literature suggests that human diseases may be affected by natural tRNA variants that cause mistranslation or de-regulate tRNA expression and nucleotide modification. This review highlights examples relevant to genetic disorders, cancer, and neurodegeneration in which cytoplasmic tRNA variants directly cause or exacerbate disease and disease-linked phenotypes in cells, animal models, and humans. In the near future, tRNAs may be recognized as useful genetic markers to predict the onset or severity of human disease. This work was supported in part by Natural Sciences and Engineering Research Council of Canada Grants RGPIN 04282-2014 (to P. O.), 530175-2018 (to P. O.), and RGPIN-2015-04394 (to C. J. B.); Canada Foundation for Innovation Grant 229917 (to P. O.); the Ontario Research Fund 229917 (to P. O.); Canada Research Chairs 950-229917 (to P. O.); and the Ontario Centres of Excellence Grant 28922 (to P. O.). This is the first article in the "tRNAs and aminoacyl-tRNA synthetases in human disease" JBC Reviews series. The authors declare that they have no conflicts of interest with the contents of this article. This article contains Tables S1 and S2 and supporting Refs. 1-8. 1 Recipient of a Postgraduate Studies Doctoral Scholarship and supported by the Natural Sciences and Engineering Research Council of Canada. 2 Recipient of a(Canada Graduate Scholarship and supported by the Natural Sciences and Engineering Research Council of Canada and by generous donations from Graham Wright and James Robertson.

Targeted sequencing reveals expanded genetic diversity of human transfer RNAs

“…One example of this is the synergistic effect of a point mutation in tRNA Arg , which enhances neurodegeneration caused by a mutant GTPBP2 gene, a ribosome recycling factor, in mice [27]. The same tRNA Arg mutation is also found in the human population [26]. The hypothesis is further supported by the association of tRNA modifying enzymes and error prone tRNA synthetases with disease.…”

“…tRNA variants that result in loss of function may impact translation fidelity or protein synthesis rates by altering cellular tRNA pools [26]. Eukaryotic tRNAs are transcribed by RNA polymerase III and require internal A and B box promoters for expression.…”

“…Due to their complex molecular interactions, single nucleotide changes in tRNAs can result in loss or gain of function that impact the composition and fidelity of the proteome. Mutations of both types have already been linked to disease in mice and humans [23][24][25][26]. For example, a mutation in a brain-specific tRNA Arg gene causes neurodegeneration in mice when combined with a second mutation in GTPBP2, a gene involved in ribosome recycling [27].…”

A Synthetic Reporter for Probing Mistranslation in Living Cells

“…Thus, traditionally, protein mistranslation is thought to be harmful or lethal to cells. Indeed, it causes a wide range of human diseases including neurological disorders, developmental disorders, viral infections, and cancers (Schimmel, 2008;Kapur and Ackerman, 2018;Lant et al, 2019;Ou et al, 2019). However, very recently, a number of studies have shown that protein mistranslation is not always detrimental (Pan, 2013;Ribas de Pouplana et al, 2014;Steiner and Ibba, 2019).…”

Computational Structural Biology: Successes, Future Directions, and Challenges

“…Inspired by Da Vinci’s imagination, a symposium has even been organized on modeling and imaging the whole human body at the atomic scale to understand the human body (). Computational biology has successfully identified disease-linked genes [18,19,20] and harnessed artificial intelligence neuron connectivity and electrical flow to model the brain. The sequencing of individuals has permitted comparisons of corresponding sequences in diseased and healthy tissues, and with the help of computational biology, technological advances have accomplished the imaging and tracking of molecules in action in single cells [21,22,23].…”