Modification of orthogonal tRNAs: unexpected consequences for sense codon reassignment

Biddle, Wil; Schmitt, Margaret A.; Fisk, John D.

doi:10.1093/nar/gkw948

Cited by 20 publications

(41 citation statements)

References 48 publications

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“…In the case of tRNA Asn , A34I would incorporate Asn at Lys AAA codons. This type of phenomenon was recently examined with anticodon variants of Methanocaldococcus jannaschii tRNA Tyr expressed in E. coli (89,90). In this case, a tRNA Tyr mutant with an AUG anticodon decoded histidine CAU and CAC codons with tyrosine at approximately equal efficiency (2-3%); the mutant tRNA Tyr AUG anticodon was indeed partially modified to IUG (89).…”

Section: Trna Variation In Humansmentioning

confidence: 99%

Pathways to disease from natural variations in human cytoplasmic tRNAs

Lant

Berg

Heinemann

et al. 2019

Journal of Biological Chemistry

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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.

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Section: Trna Variation In Humansmentioning

confidence: 99%

Pathways to disease from natural variations in human cytoplasmic tRNAs

Lant

Berg

Heinemann

et al. 2019

Journal of Biological Chemistry

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“…Also, the role of heterologous tRNA post-transcriptional modifications is emerging as a considerable factor in improving o-tRNA proficiency [30–32]. In cases when poor tRNA orthogonality impedes negative selection (Figure 1c), parallel positive selection schemes may be developed [33 •• ].…”

Section: Efficiency Of O-aars•trna Pairsmentioning

confidence: 99%

Upgrading aminoacyl-tRNA synthetases for genetic code expansion

Vargas-Rodriguez

Sevostyanova

Söll

et al. 2018

Current Opinion in Chemical Biology

106

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Synthesis of proteins with non-canonical amino acids via genetic code expansion is at the forefront of synthetic biology. Progress in this field has enabled site-specific incorporation of over 200 chemically and structurally diverse amino acids into proteins in an increasing number of organisms. This has been facilitated by our ability to repurpose aminoacyl-tRNA synthetases to attach non-canonical amino acids to engineered tRNAs. Current efforts in the field focus on overcoming existing limitations to the simultaneous incorporation of multiple non-canonical amino acids or amino acids that differ from the l-α-amino acid structure (e.g. d-amino acid or β-amino acid). Here, we summarize the progress and challenges in developing more selective and efficient aminoacyl-tRNA synthetases for genetic code expansion.

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“…In contrast, modified C34 derivatives can be paired with adenine (101, 133). Studies on modification of orthogonal tRNAs have just started (9), but they could provide opportunities to expand the genetic code by splitting anticodons (70). …”

Section: Preparing For Radically Altered Genetic Codesmentioning

confidence: 99%

Rewriting the Genetic Code

Mukai

Lajoie

Englert

et al. 2017

Annu. Rev. Microbiol.

145

137

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The genetic code—the language used by cells to translate their genomes into proteins that perform many cellular functions—is highly conserved throughout natural life. Rewriting the genetic code could lead to new biological functions such as expanding protein chemistries with noncanonical amino acids (ncAAs) and genetically isolating synthetic organisms from natural organisms and viruses. It has long been possible to transiently produce proteins bearing ncAAs, but stabilizing an expanded genetic code for sustained function in vivo requires an integrated approach: creating recoded genomes and introducing new translation machinery that function together without compromising viability or clashing with endogenous pathways. In this review, we discuss design considerations and technologies for expanding the genetic code. The knowledge obtained by rewriting the genetic code will deepen our understanding of how genomes are designed and how the canonical genetic code evolved.

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Modification of orthogonal tRNAs: unexpected consequences for sense codon reassignment

Cited by 20 publications

References 48 publications

Pathways to disease from natural variations in human cytoplasmic tRNAs

Pathways to disease from natural variations in human cytoplasmic tRNAs

Upgrading aminoacyl-tRNA synthetases for genetic code expansion

Rewriting the Genetic Code

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