Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The expanding world of tRNA modifications and their disease relevance

Abstract

Transfer RNA (tRNA) is an adapter molecule that links a specific codon in mRNA with its corresponding amino acid during protein synthesis. tRNAs are enzymatically modified post-transcriptionally. A wide variety of tRNA modifications are found in the tRNA anticodon, which are crucial for precise codon recognition and reading frame maintenance, thereby ensuring accurate and efficient protein synthesis. In addition, tRNA-body regions are also frequently modified and thus stabilized in the cell. Over the past two decades, 16 novel tRNA modifications were discovered in various organisms, and the chemical space of tRNA modification continues to expand. Recent studies have revealed that tRNA modifications can be dynamically altered in response to levels of cellular metabolites and environmental stresses. Importantly, we now understand that deficiencies in tRNA modification can have pathological consequences, which are termed ‘RNA modopathies’. Dysregulation of tRNA modification is involved in mitochondrial diseases, neurological disorders and cancer.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Basic structure and function of tRNA.
Fig. 2: Integrated view of human tRNA modifications.
Fig. 3: tRNA modifications discovered in the past two decades.
Fig. 4: Control of decoding by tRNA wobble modifications.
Fig. 5: Metabolic and pathological regulation tRNA modifications in human mitochondria.
Fig. 6: Cellular CO2 concentration regulates the level of t6A.
Fig. 7: Codon-specific translation control mediated by tRNA modifications in cancer.

References

  1. 1.

    Holley, R. W. et al. Structure of a ribonucleic acid. Science 147, 1462–1465 (1965).

    CAS  PubMed  Google Scholar 

  2. 2.

    Crick, F. H. Codon–anticodon pairing: the wobble hypothesis. J. Mol. Biol. 19, 548–555 (1966).

    CAS  PubMed  Google Scholar 

  3. 3.

    Ogle, J. M., Murphy, F. V., Tarry, M. J. & Ramakrishnan, V. Selection of tRNA by the ribosome requires a transition from an open to a closed form. Cell 111, 721–732 (2002).

    CAS  PubMed  Google Scholar 

  4. 4.

    Suzuki, T. in Fine-Tuning of RNA Functions by Modification and Editing, Vol. 12 (ed. Grosjean, H.) 23–69 (Springer-Verlag, 2005).

  5. 5.

    Agris, P. F. et al. Celebrating wobble decoding: half a century and still much is new. RNA Biol. 15, 537–553 (2018).

    PubMed  Google Scholar 

  6. 6.

    Han, L. & Phizicky, E. M. A rationale for tRNA modification circuits in the anticodon loop. RNA 24, 1277–1284 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Bjork, G. R., Wikstrom, P. M. & Bystrom, A. S. Prevention of translational frameshifting by the modified nucleoside 1-methylguanosine. Science 244, 986–989 (1989).

    CAS  PubMed  Google Scholar 

  8. 8.

    Helm, M. & Alfonzo, J. D. Posttranscriptional RNA modifications: playing metabolic games in a cell’s chemical Legoland. Chem. Biol. 21, 174–185 (2014).

    CAS  PubMed  Google Scholar 

  9. 9.

    Motorin, Y. & Helm, M. tRNA stabilization by modified nucleotides. Biochemistry 49, 4934–4944 (2010).

    CAS  PubMed  Google Scholar 

  10. 10.

    Sylvers, L. A., Rogers, K. C., Shimizu, M., Ohtsuka, E. & Soll, D. A 2-thiouridine derivative in tRNAGlu is a positive determinant for aminoacylation by Escherichia coli glutamyl-tRNA synthetase. Biochemistry 32, 3836–3841 (1993).

    CAS  PubMed  Google Scholar 

  11. 11.

    Suzuki, T., Ueda, T. & Watanabe, K. The ‘polysemous’ codon–a codon with multiple amino acid assignment caused by dual specificity of tRNA identity. EMBO J. 16, 1122–1134 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Voorhees, R. M. & Ramakrishnan, V. Structural basis of the translational elongation cycle. Annu. Rev. Biochem. 82, 203–236 (2013).

    CAS  PubMed  Google Scholar 

  13. 13.

    Florentz, C. & Giege, R. History of tRNA research in Strasbourg. IUBMB Life 71, 1066–1087 (2019).

    CAS  PubMed  Google Scholar 

  14. 14.

    Ibba, M. & Soll, D. Aminoacyl-tRNA synthesis. Annu. Rev. Biochem. 69, 617–650 (2000).

    CAS  PubMed  Google Scholar 

  15. 15.

    McClain, W. H. Rules that govern tRNA identity in protein synthesis. J. Mol. Biol. 234, 257–280 (1993).

    CAS  PubMed  Google Scholar 

  16. 16.

    Muramatsu, T. et al. Codon and amino-acid specificities of a transfer RNA are both converted by a single post-transcriptional modification. Nature 336, 179–181 (1988).

    CAS  PubMed  Google Scholar 

  17. 17.

    Senger, B., Auxilien, S., Englisch, U., Cramer, F. & Fasiolo, F. The modified wobble base inosine in yeast tRNAIle is a positive determinant for aminoacylation by isoleucyl-tRNA synthetase. Biochemistry 36, 8269–8275 (1997).

    CAS  PubMed  Google Scholar 

  18. 18.

    Thiaville, P. C. et al. Essentiality of threonylcarbamoyladenosine (t6A), a universal tRNA modification, in bacteria. Mol. Microbiol. 98, 1199–1221 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Niimi, T. et al. Recognition of the anticodon loop of tRNAIle1 by isoleucyl-transfer RNA synthetase from Escherichia coli. Nucleosides Nucleotides Nucleic Acids 13, 1231–1237 (1994).

    CAS  Google Scholar 

  20. 20.

    Putz, J., Florentz, C., Benseler, F. & Giege, R. A single methyl group prevents the mischarging of a tRNA. Nat. Struct. Biol. 1, 580–582 (1994).

    CAS  PubMed  Google Scholar 

  21. 21.

    Uhlenbeck, O. C. & Schrader, J. M. Evolutionary tuning impacts the design of bacterial tRNAs for the incorporation of unnatural amino acids by ribosomes. Curr. Opin. Chem. Biol. 46, 138–145 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    LaRiviere, F. J., Wolfson, A. D. & Uhlenbeck, O. C. Uniform binding of aminoacyl-tRNAs to elongation factor Tu by thermodynamic compensation. Science 294, 165–168 (2001).

    CAS  PubMed  Google Scholar 

  23. 23.

    Asahara, H. & Uhlenbeck, O. C. Predicting the binding affinities of misacylated tRNAs for Thermus thermophilus EF-Tu.GTP. Biochemistry 44, 11254–11261 (2005).

    CAS  PubMed  Google Scholar 

  24. 24.

    Lorenz, C., Lunse, C. E. & Morl, M. tRNA modifications: impact on structure and thermal adaptation. Biomolecules 7, 35 (2017).

    PubMed Central  Google Scholar 

  25. 25.

    Zhou, D., Tanzawa, T., Lin, J. & Gagnon, M. G. Structural basis for ribosome recycling by RRF and tRNA. Nat. Struct. Mol. Biol. 27, 25–32 (2020).

    CAS  PubMed  Google Scholar 

  26. 26.

    Boccaletto, P. et al. MODOMICS: a database of RNA modification pathways. 2017 update. Nucleic Acids Res. 46, D303–D307 (2018).

    CAS  PubMed  Google Scholar 

  27. 27.

    Juhling, F. et al. tRNAdb 2009: compilation of tRNA sequences and tRNA genes. Nucleic Acids Res. 37, D159–D162 (2009).

    PubMed  Google Scholar 

  28. 28.

    Frye, M., Jaffrey, S. R., Pan, T., Rechavi, G. & Suzuki, T. RNA modifications: what have we learned and where are we headed? Nat. Rev. Genet. 17, 365–372 (2016).

    CAS  PubMed  Google Scholar 

  29. 29.

    Alfonzo, J. D. Post-transcriptional modifications are very important after all. RNA Biol. 11, 1481–1482 (2014).

    PubMed  Google Scholar 

  30. 30.

    Grosjean, H. in Fine-Tuning of RNA Functions by Modification and Editing, Vol. 12 (ed. Grosjean, H.) 1–22 (Springer-Verlag, 2005).

  31. 31.

    Chan, P. P. & Lowe, T. M. GtRNAdb 2.0: an expanded database of transfer RNA genes identified in complete and draft genomes. Nucleic Acids Res. 44, D184–D189 (2016).

    CAS  PubMed  Google Scholar 

  32. 32.

    Kutter, C. et al. Pol III binding in six mammals shows conservation among amino acid isotypes despite divergence among tRNA genes. Nat. Genet. 43, 948–955 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Gogakos, T. et al. Characterizing expression and processing of precursor and mature human tRNAs by hydro-tRNAseq and PAR-CLIP. Cell Rep. 20, 1463–1475 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Cozen, A. E. et al. ARM-seq: AlkB-facilitated RNA methylation sequencing reveals a complex landscape of modified tRNA fragments. Nat. Methods 12, 879–884 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Zheng, G. et al. Efficient and quantitative high-throughput tRNA sequencing. Nat. Methods 12, 835–837 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Hoffmann, A. et al. Accurate mapping of tRNA reads. Bioinformatics 34, 1116–1124 (2018).

    CAS  PubMed  Google Scholar 

  37. 37.

    Pinkard, O., McFarland, S., Sweet, T. & Coller, J. Quantitative tRNA-sequencing uncovers metazoan tissue-specific tRNA regulation. Nat. Commun. 11, 4104 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Li, X., Xiong, X. & Yi, C. Epitranscriptome sequencing technologies: decoding RNA modifications. Nat. Methods 14, 23–31 (2016).

    PubMed  Google Scholar 

  39. 39.

    Wang, J., Toffano-Nioche, C., Lorieux, F., Gautheret, D. & Lehmann, J. Accurate characterization of Escherichia coli tRNA modifications with a simple method of deep-sequencing library preparation. RNA Biol. https://doi.org/10.1080/15476286.2020.1790871 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Clark, W. C., Evans, M. E., Dominissini, D., Zheng, G. & Pan, T. tRNA base methylation identification and quantification via high-throughput sequencing. RNA 22, 1771–1784 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Song, J. et al. Differential roles of human PUS10 in miRNA processing and tRNA pseudouridylation. Nat. Chem. Biol. 16, 160–169 (2020).

    CAS  PubMed  Google Scholar 

  42. 42.

    Kimura, S., Dedon, P. C. & Waldor, M. K. Comparative tRNA sequencing and RNA mass spectrometry for surveying tRNA modifications. Nat. Chem. Biol. 16, 964–972 (2020).

    CAS  PubMed  Google Scholar 

  43. 43.

    Suzuki, T., Nagao, A. & Suzuki, T. Human mitochondrial tRNAs: biogenesis, function, structural aspects, and diseases. Annu. Rev. Genet. 45, 299–329 (2011).

    CAS  PubMed  Google Scholar 

  44. 44.

    Suzuki, T. et al. Complete chemical structures of human mitochondrial tRNAs. Nat. Commun. 11, 4269 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Marcus, J. O. & Bystrom, A. in Fine-Tuning of RNA Functions by Modification and Editing, Vol. 12 (ed. Grosjean, H.) 87–120 (Springer-Verlag, 2005).

  46. 46.

    Yoshida, M. et al. Rectifier of aberrant mRNA splicing recovers tRNA modification in familial dysautonomia. Proc. Natl Acad. Sci. USA 112, 2764–2769 (2015).

    CAS  PubMed  Google Scholar 

  47. 47.

    Suzuki, T., Suzuki, T., Wada, T., Saigo, K. & Watanabe, K. Taurine as a constituent of mitochondrial tRNAs: new insights into the functions of taurine and human mitochondrial diseases. EMBO J. 21, 6581–6589 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Asano, K. et al. Metabolic and chemical regulation of tRNA modification associated with taurine deficiency and human disease. Nucleic Acids Res. 46, 1565–1583 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Yokoyama, S. et al. Molecular mechanism of codon recognition by tRNA species with modified uridine in the first position of the anticodon. Proc. Natl Acad. Sci. USA 82, 4905–4909 (1985).

    CAS  PubMed  Google Scholar 

  50. 50.

    Kurata, S. et al. Modified uridines with C5-methylene substituents at the first position of the tRNA anticodon stabilize U·G wobble pairing during decoding. J. Biol. Chem. 283, 18801–18811 (2008).

    CAS  PubMed  Google Scholar 

  51. 51.

    Kirino, Y. et al. Codon-specific translational defect caused by a wobble modification deficiency in mutant tRNA from a human mitochondrial disease. Proc. Natl Acad. Sci. USA 101, 15070–15075 (2004).

    CAS  PubMed  Google Scholar 

  52. 52.

    Johansson, M. J., Esberg, A., Huang, B., Bjork, G. R. & Bystrom, A. S. Eukaryotic wobble uridine modifications promote a functionally redundant decoding system. Mol. Cell. Biol. 28, 3301–3312 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Yasukawa, T., Suzuki, T., Ishii, N., Ohta, S. & Watanabe, K. Wobble modification defect in tRNA disturbs codon-anticodon interaction in a mitochondrial disease. EMBO J. 20, 4794–4802 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Tukenmez, H., Xu, H., Esberg, A. & Bystrom, A. S. The role of wobble uridine modifications in +1 translational frameshifting in eukaryotes. Nucleic Acids Res. 43, 9489–9499 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Murphy, F. V. T., Ramakrishnan, V., Malkiewicz, A. & Agris, P. F. The role of modifications in codon discrimination by tRNALysUUU. Nat. Struct. Mol. Biol. 11, 1186–1191 (2004).

    CAS  PubMed  Google Scholar 

  56. 56.

    Zinshteyn, B. & Gilbert, W. V. Loss of a conserved tRNA anticodon modification perturbs cellular signaling. PLoS Genet. 9, e1003675 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Nedialkova, D. D. & Leidel, S. A. Optimization of codon translation rates via tRNA modifications maintains proteome integrity. Cell 161, 1606–1618 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Phelps, S. S., Malkiewicz, A., Agris, P. F. & Joseph, S. Modified nucleotides in tRNALys and tRNAVal are important for translocation. J. Mol. Biol. 338, 439–444 (2004).

    CAS  PubMed  Google Scholar 

  59. 59.

    Ranjan, N. & Rodnina, M. V. Thio-modification of tRNA at the wobble position as regulator of the kinetics of decoding and translocation on the ribosome. J. Am. Chem. Soc. 139, 5857–5864 (2017).

    CAS  PubMed  Google Scholar 

  60. 60.

    Murphy, F. V. T. & Ramakrishnan, V. Structure of a purine-purine wobble base pair in the decoding center of the ribosome. Nat. Struct. Mol. Biol. 11, 1251–1252 (2004).

    CAS  PubMed  Google Scholar 

  61. 61.

    Wolf, J., Gerber, A. P. & Keller, W. tadA, an essential tRNA-specific adenosine deaminase from Escherichia coli. EMBO J. 21, 3841–3851 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Gerber, A. P. & Keller, W. An adenosine deaminase that generates inosine at the wobble position of tRNAs. Science 286, 1146–1149 (1999).

    CAS  PubMed  Google Scholar 

  63. 63.

    Torres, A. G. et al. Inosine modifications in human tRNAs are incorporated at the precursor tRNA level. Nucleic Acids Res. 43, 5145–5157 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Novoa, E. M., Pavon-Eternod, M., Pan, T. & Ribas de Pouplana, L. A role for tRNA modifications in genome structure and codon usage. Cell 149, 202–213 (2012).

    CAS  PubMed  Google Scholar 

  65. 65.

    Moriya, J. et al. A novel modified nucleoside found at the first position of the anticodon of methionine tRNA from bovine liver mitochondria. Biochemistry 33, 2234–2239 (1994).

    CAS  PubMed  Google Scholar 

  66. 66.

    Takemoto, C. et al. Unconventional decoding of the AUA codon as methionine by mitochondrial tRNAMet with the anticodon f5CAU as revealed with a mitochondrial in vitro translation system. Nucleic Acids Res. 37, 1616–1627 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Cantara, W. A., Murphy, F. V. T., Demirci, H. & Agris, P. F. Expanded use of sense codons is regulated by modified cytidines in tRNA. Proc. Natl Acad. Sci. USA 110, 10964–10969 (2013).

    CAS  PubMed  Google Scholar 

  68. 68.

    Nakano, S. et al. NSUN3 methylase initiates 5-formylcytidine biogenesis in human mitochondrial tRNAMet. Nat. Chem. Biol. 12, 546–551 (2016).

    CAS  PubMed  Google Scholar 

  69. 69.

    Van Haute, L. et al. Deficient methylation and formylation of mt-tRNAMet wobble cytosine in a patient carrying mutations in NSUN3. Nat. Commun. 7, 12039 (2016).

    PubMed  PubMed Central  Google Scholar 

  70. 70.

    Haag, S. et al. NSUN3 and ABH1 modify the wobble position of mt-tRNAMet to expand codon recognition in mitochondrial translation. EMBO J. 35, 2104–2119 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Kawarada, L. et al. ALKBH1 is an RNA dioxygenase responsible for cytoplasmic and mitochondrial tRNA modifications. Nucleic Acids Res. 45, 7401–7415 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Copela, L. A., Fernandez, C. F., Sherrer, R. L. & Wolin, S. L. Competition between the Rex1 exonuclease and the La protein affects both Trf4p-mediated RNA quality control and pre-tRNA maturation. RNA 14, 1214–1227 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Kadaba, S. et al. Nuclear surveillance and degradation of hypomodified initiator tRNAMet in S. cerevisiae. Genes Dev. 18, 1227–1240 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Alexandrov, A. et al. Rapid tRNA decay can result from lack of nonessential modifications. Mol. Cell 21, 87–96 (2006).

    CAS  PubMed  Google Scholar 

  75. 75.

    Dewe, J. M., Whipple, J. M., Chernyakov, I., Jaramillo, L. N. & Phizicky, E. M. The yeast rapid tRNA decay pathway competes with elongation factor 1A for substrate tRNAs and acts on tRNAs lacking one or more of several modifications. RNA 18, 1886–1896 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Suzuki, T., Nagano, T. & Suzuki, T. Human mitochondrial diseases caused by lack of taurine modification in mitochondrial tRNAs. Wiley Interdiscip. Rev. RNA 2, 376–386 (2011).

    CAS  PubMed  Google Scholar 

  77. 77.

    Umeda, N. et al. Mitochondria-specific RNA-modifying enzymes responsible for the biosynthesis of the wobble base in mitochondrial tRNAs. Implications for the molecular pathogenesis of human mitochondrial diseases. J. Biol. Chem. 280, 1613–1624 (2005).

    CAS  PubMed  Google Scholar 

  78. 78.

    Huxtable, R. J. Physiological actions of taurine. Physiol. Rev. 72, 101–163 (1992).

    CAS  PubMed  Google Scholar 

  79. 79.

    Bouckenooghe, T., Remacle, C. & Reusens, B. Is taurine a functional nutrient? Curr. Opin. Clin. Nutr. Metab. Care 9, 728–733 (2006).

    CAS  PubMed  Google Scholar 

  80. 80.

    Verbrugghe, A. & Bakovic, M. Peculiarities of one-carbon metabolism in the strict carnivorous cat and the role in feline hepatic lipidosis. Nutrients 5, 2811–2835 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Morris, J. G. Idiosyncratic nutrient requirements of cats appear to be diet-induced evolutionary adaptations. Nutr. Res. Rev. 15, 153–168 (2002).

    CAS  PubMed  Google Scholar 

  82. 82.

    Schaffer, S. W., Jong, C. J., Warner, D., Ito, T. & Azuma, J. Taurine deficiency and MELAS are closely related syndromes. Adv. Exp. Med. Biol. 776, 153–165 (2013).

    CAS  PubMed  Google Scholar 

  83. 83.

    Sturman, J. A. Taurine in development. Physiol. Rev. 73, 119–147 (1993).

    CAS  PubMed  Google Scholar 

  84. 84.

    Seikai, T., Takeuchi, T. & Park, G. S. Comparison of growth, feed efficiency, and chemical composition of juvenile flounder fed live mysids and formula feed under laboratory conditions. Fish. Sci. 63, 520–526 (1997).

    CAS  Google Scholar 

  85. 85.

    Sochacka, E. et al. C5-substituents of uridines and 2-thiouridines present at the wobble position of tRNA determine the formation of their keto-enol or zwitterionic forms - a factor important for accuracy of reading of guanosine at the 3-end of the mRNA codons. Nucleic Acids Res. 45, 4825–4836 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Kikuchi, G., Motokawa, Y., Yoshida, T. & Hiraga, K. Glycine cleavage system: reaction mechanism, physiological significance, and hyperglycinemia. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 84, 246–263 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Ducker, G. S. & Rabinowitz, J. D. One-carbon metabolism in health and disease. Cell Metab. 25, 27–42 (2017).

    CAS  PubMed  Google Scholar 

  88. 88.

    Morscher, R. J. et al. Mitochondrial translation requires folate-dependent tRNA methylation. Nature 554, 128–132 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Ye, J. et al. Serine catabolism regulates mitochondrial redox control during hypoxia. Cancer Discov. 4, 1406–1417 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Woo, C. C., Chen, W. C., Teo, X. Q., Radda, G. K. & Lee, P. T. Downregulating serine hydroxymethyltransferase 2 (SHMT2) suppresses tumorigenesis in human hepatocellular carcinoma. Oncotarget 7, 53005–53017 (2016).

    PubMed  PubMed Central  Google Scholar 

  91. 91.

    Hashizume, O. et al. Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confers human age-associated mitochondrial respiration defects. Sci. Rep. 5, 10434 (2015).

    PubMed  PubMed Central  Google Scholar 

  92. 92.

    Molloy, A. M. Folate bioavailability and health. Int. J. Vitam. Nutr. Res. 72, 46–52 (2002).

    CAS  PubMed  Google Scholar 

  93. 93.

    Thiaville, P. C., Iwata-Reuyl, D. & de Crecy-Lagard, V. Diversity of the biosynthesis pathway for threonylcarbamoyladenosine (t6A), a universal modification of tRNA. RNA Biol. 11, 1529–1539 (2014).

    PubMed  Google Scholar 

  94. 94.

    Schweizer, M. P., Chheda, G. B., Baczynskyj, L. & Hall, R. H. Aminoacyl nucleosides. VII. N-(Purin-6-ylcarbamoyl)threonine. A new component of transfer ribonucleic acid. Biochemistry 8, 3283–3289 (1969).

    CAS  PubMed  Google Scholar 

  95. 95.

    Rozov, A., Demeshkina, N., Westhof, E., Yusupov, M. & Yusupova, G. Structural insights into the translational infidelity mechanism. Nat. Commun. 6, 7251 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Srinivasan, M. et al. The highly conserved KEOPS/EKC complex is essential for a universal tRNA modification, t6A. EMBO J. 30, 873–881 (2011).

    CAS  PubMed  Google Scholar 

  97. 97.

    El Yacoubi, B. et al. A role for the universal Kae1/Qri7/YgjD (COG0533) family in tRNA modification. EMBO J. 30, 882–893 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Lin, H. et al. CO2-sensitive tRNA modification associated with human mitochondrial disease. Nat. Commun. 9, 1875 (2018).

    PubMed  PubMed Central  Google Scholar 

  99. 99.

    Smith, D. G., Pal, R. & Parker, D. Measuring equilibrium bicarbonate concentrations directly in cellular mitochondria and in human serum using europium/terbium emission intensity ratios. Chemistry 18, 11604–11613 (2012).

    CAS  PubMed  Google Scholar 

  100. 100.

    Semenza, G. L. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 3, 721–732 (2003).

    CAS  PubMed  Google Scholar 

  101. 101.

    Benej, M. et al. Carbonic anhydrase IX: regulation and role in cancer. Subcell. Biochem. 75, 199–219 (2014).

    CAS  PubMed  Google Scholar 

  102. 102.

    Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029–1033 (2009).

    Google Scholar 

  103. 103.

    Nishimura, S. Structure, biosynthesis, and function of queuosine in transfer RNA. Prog. Nucleic Acid Res. Mol. Biol. 28, 49–73 (1983).

    CAS  PubMed  Google Scholar 

  104. 104.

    Kasai, H., Kuchino, Y., Nihei, K. & Nishimura, S. Distribution of the modified nucleoside Q and its derivatives in animal and plant transfer RNA’s. Nucleic Acids Res. 2, 1931–1939 (1975).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Iwata-Reuyl, D. Biosynthesis of the 7-deazaguanosine hypermodified nucleosides of transfer RNA. Bioorg Chem. 31, 24–43 (2003).

    CAS  PubMed  Google Scholar 

  106. 106.

    Marks, T. & Farkas, W. R. Effects of a diet deficient in tyrosine and queuine on germfree mice. Biochem. Biophys. Res. Commun. 230, 233–237 (1997).

    CAS  PubMed  Google Scholar 

  107. 107.

    Farkas, W. R. Effect of diet on the queuosine family of tRNAs of germ-free mice. J. Biol. Chem. 255, 6832–6835 (1980).

    CAS  PubMed  Google Scholar 

  108. 108.

    Hatfield, D. et al. Chromatographic analysis of the aminoacyl-tRNAs which are required for translation of codons at and around the ribosomal frameshift sites of HIV, HTLV-1, and BLV. Virology 173, 736–742 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Muller, M. et al. Queuine links translational control in eukaryotes to a micronutrient from bacteria. Nucleic Acids Res. 47, 3711–3727 (2019).

    PubMed  PubMed Central  Google Scholar 

  110. 110.

    Tuorto, F. et al. Queuosine-modified tRNAs confer nutritional control of protein translation. EMBO J. 37, e99777 (2018).

    PubMed  PubMed Central  Google Scholar 

  111. 111.

    Iwata-Reuyl, D. & de Crecy-Lagard, V. in DNA and RNA Modification Enzymes: Structure, Mechanism, Function and Evolution, 377–391 (Landes Bioscience, 2009).

  112. 112.

    Chen, Y. C., Kelly, V. P., Stachura, S. V. & Garcia, G. A. Characterization of the human tRNA-guanine transglycosylase: confirmation of the heterodimeric subunit structure. RNA 16, 958–968 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Boland, C., Hayes, P., Santa-Maria, I., Nishimura, S. & Kelly, V. P. Queuosine formation in eukaryotic tRNA occurs via a mitochondria-localized heteromeric transglycosylase. J. Biol. Chem. 284, 18218–18227 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Rakovich, T. et al. Queuosine deficiency in eukaryotes compromises tyrosine production through increased tetrahydrobiopterin oxidation. J. Biol. Chem. 286, 19354–19363 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Hanson, G. & Coller, J. Codon optimality, bias and usage in translation and mRNA decay. Nat. Rev. Mol. Cell Biol. 19, 20–30 (2018).

    CAS  PubMed  Google Scholar 

  116. 116.

    Gorman, G. S. et al. Mitochondrial diseases. Nat. Rev. Dis. Prim. 2, 16080 (2016).

    PubMed  Google Scholar 

  117. 117.

    Wallace, D. C. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu. Rev. Genet. 39, 359–407 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Pavlakis, S. G., Phillips, P. C., DiMauro, S., De Vivo, D. C. & Rowland, L. P. Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes: a distinctive clinical syndrome. Ann. Neurol. 16, 481–488 (1984).

    CAS  PubMed  Google Scholar 

  119. 119.

    Fukuhara, N., Tokiguchi, S., Shirakawa, K. & Tsubaki, T. Myoclonus epilepsy associated with ragged-red fibres (mitochondrial abnormalities): disease entity or a syndrome? Light-and electron-microscopic studies of two cases and review of literature. J. Neurol. Sci. 47, 117–133 (1980).

    CAS  PubMed  Google Scholar 

  120. 120.

    Goto, Y., Nonaka, I. & Horai, S. A mutation in the tRNALeu(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348, 651–653 (1990).

    CAS  PubMed  Google Scholar 

  121. 121.

    Shoffner, J. M. et al. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNALys mutation. Cell 61, 931–937 (1990).

    CAS  PubMed  Google Scholar 

  122. 122.

    Goto, Y., Nonaka, I. & Horai, S. A new mtDNA mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). Biochim. Biophys. Acta 1097, 238–240 (1991).

    CAS  PubMed  Google Scholar 

  123. 123.

    Kelley, S. O., Steinberg, S. V. & Schimmel, P. Functional defects of pathogenic human mitochondrial tRNAs related to structural fragility. Nat. Struct. Biol. 7, 862–865 (2000).

    CAS  PubMed  Google Scholar 

  124. 124.

    Yasukawa, T. et al. Modification defect at anticodon wobble nucleotide of mitochondrial tRNAsLeu(UUR) with pathogenic mutations of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes. J. Biol. Chem. 275, 4251–4257 (2000).

    CAS  PubMed  Google Scholar 

  125. 125.

    Kirino, Y., Goto, Y., Campos, Y., Arenas, J. & Suzuki, T. Specific correlation between the wobble modification deficiency in mutant tRNAs and the clinical features of a human mitochondrial disease. Proc. Natl Acad. Sci. USA 102, 7127–7132 (2005).

    CAS  PubMed  Google Scholar 

  126. 126.

    Yasukawa, T. et al. Wobble modification deficiency in mutant tRNAs in patients with mitochondrial diseases. FEBS Lett. 579, 2948–2952 (2005).

    CAS  PubMed  Google Scholar 

  127. 127.

    Yasukawa, T. et al. Defect in modification at the anticodon wobble nucleotide of mitochondrial tRNALys with the MERRF encephalomyopathy pathogenic mutation. FEBS Lett. 467, 175–178 (2000).

    CAS  PubMed  Google Scholar 

  128. 128.

    Richter, U. et al. RNA modification landscape of the human mitochondrial tRNALys regulates protein synthesis. Nat. Commun. 9, 3966 (2018).

    PubMed  PubMed Central  Google Scholar 

  129. 129.

    Hayashi, J. et al. Accumulation of mtDNA with a mutation at position 3271 in tRNALeu(UUR) gene introduced from a MELAS patient to HeLa cells lacking mtDNA results in progressive inhibition of mitochondrial respiratory function. Biochem. Biophys. Res. Commun. 197, 1049–1055 (1993).

    CAS  PubMed  Google Scholar 

  130. 130.

    Dunbar, D. R., Moonie, P. A., Zeviani, M. & Holt, I. J. Complex I deficiency is associated with 3243G:C mitochondrial DNA in osteosarcoma cell cybrids. Hum. Mol. Genet. 5, 123–129 (1996).

    CAS  PubMed  Google Scholar 

  131. 131.

    Rikimaru, M. et al. Taurine ameliorates impaired the mitochondrial function and prevents stroke-like episodes in patients with MELAS. Intern. Med. 51, 3351–3357 (2012).

    PubMed  Google Scholar 

  132. 132.

    Ohsawa, Y. et al. Taurine supplementation for prevention of stroke-like episodes in MELAS: a multicentre, open-label, 52-week phase III trial. J. Neurol. Neurosurg. Psychiatry 90, 529–536 (2019).

    PubMed  Google Scholar 

  133. 133.

    Torres, A. G., Batlle, E. & Ribas de Pouplana, L. Role of tRNA modifications in human diseases. Trends Mol. Med. 20, 306–314 (2014).

    CAS  PubMed  Google Scholar 

  134. 134.

    Ramos, J. & Fu, D. The emerging impact of tRNA modifications in the brain and nervous system. Biochim. Biophys. Acta Gene Regul. Mech. 1862, 412–428 (2019).

    CAS  PubMed  Google Scholar 

  135. 135.

    Ghezzi, D. et al. Mutations of the mitochondrial-tRNA modifier MTO1 cause hypertrophic cardiomyopathy and lactic acidosis. Am. J. Hum. Genet. 90, 1079–1087 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Baruffini, E. et al. MTO1 mutations are associated with hypertrophic cardiomyopathy and lactic acidosis and cause respiratory chain deficiency in humans and yeast. Hum. Mutat. 34, 1501–1509 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Fakruddin, M. et al. Defective mitochondrial tRNA taurine modification activates global proteostress and leads to mitochondrial disease. Cell Rep. 22, 482–496 (2018).

    CAS  PubMed  Google Scholar 

  138. 138.

    Kopajtich, R. et al. Mutations in GTPBP3 cause a mitochondrial translation defect associated with hypertrophic cardiomyopathy, lactic acidosis, and encephalopathy. Am. J. Hum. Genet. 95, 708–720 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Zeharia, A. et al. Acute infantile liver failure due to mutations in the TRMU gene. Am. J. Hum. Genet. 85, 401–407 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Wu, Y. et al. Mtu1-mediated thiouridine formation of mitochondrial tRNAs is required for mitochondrial translation and is involved in reversible infantile liver injury. PLoS Genet. 12, e1006355 (2016).

    PubMed  PubMed Central  Google Scholar 

  141. 141.

    Paramasivam, A., Meena, A. K., Venkatapathi, C., Pitceathly, R. D. S. & Thangaraj, K. Novel biallelic NSUN3 variants cause early-onset mitochondrial encephalomyopathy and seizures. J. Mol. Neurosci. 70, 1962–1965 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Patton, J. R., Bykhovskaya, Y., Mengesha, E., Bertolotto, C. & Fischel-Ghodsian, N. Mitochondrial myopathy and sideroblastic anemia (MLASA): missense mutation in the pseudouridine synthase 1 (PUS1) gene is associated with the loss of tRNA pseudouridylation. J. Biol. Chem. 280, 19823–19828 (2005).

    CAS  PubMed  Google Scholar 

  143. 143.

    Mangum, J. E. et al. Pseudouridine synthase 1 deficient mice, a model for mitochondrial myopathy with sideroblastic anemia, exhibit muscle morphology and physiology alterations. Sci. Rep. 6, 26202 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Carlile, T. M. et al. mRNA structure determines modification by pseudouridine synthase 1. Nat. Chem. Biol. 15, 966–974 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Zhao, X. et al. Regulation of nuclear receptor activity by a pseudouridine synthase through posttranscriptional modification of steroid receptor RNA activator. Mol. Cell 15, 549–558 (2004).

    CAS  PubMed  Google Scholar 

  146. 146.

    Karijolich, J., Yi, C. & Yu, Y. T. Transcriptome-wide dynamics of RNA pseudouridylation. Nat. Rev. Mol. Cell Biol. 16, 581–585 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Riley, C. M. et al. Central autonomic dysfunction with defective lacrimation; report of five cases. Pediatrics 3, 468–478 (1949).

    CAS  PubMed  Google Scholar 

  148. 148.

    Norcliffe-Kaufmann, L., Slaugenhaupt, S. A. & Kaufmann, H. Familial dysautonomia: history, genotype, phenotype and translational research. Prog. Neurobiol. 152, 131–148 (2017).

    PubMed  Google Scholar 

  149. 149.

    Anderson, S. L. et al. Familial dysautonomia is caused by mutations of the IKAP gene. Am. J. Hum. Genet. 68, 753–758 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Huang, B., Johansson, M. J. & Bystrom, A. S. An early step in wobble uridine tRNA modification requires the elongator complex. RNA 11, 424–436 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Johansson, M. J. O., Xu, F. & Bystrom, A. S. Elongator-a tRNA modifying complex that promotes efficient translational decoding. Biochim. Biophys. Acta Gene Regul. Mech. 1861, 401–408 (2018).

    CAS  PubMed  Google Scholar 

  152. 152.

    Krutyholowa, R., Zakrzewski, K. & Glatt, S. Charging the code - tRNA modification complexes. Curr. Opin. Struct. Biol. 55, 138–146 (2019).

    CAS  PubMed  Google Scholar 

  153. 153.

    Karlsborn, T., Tukenmez, H., Chen, C. & Bystrom, A. S. Familial dysautonomia (FD) patients have reduced levels of the modified wobble nucleoside mcm5s2U in tRNA. Biochem. Biophys. Res. Commun. 454, 441–445 (2014).

    CAS  PubMed  Google Scholar 

  154. 154.

    Chen, Y. T. et al. Loss of mouse Ikbkap, a subunit of elongator, leads to transcriptional deficits and embryonic lethality that can be rescued by human IKBKAP. Mol. Cell. Biol. 29, 736–744 (2009).

    CAS  PubMed  Google Scholar 

  155. 155.

    Cohen, J. S. et al. ELP2 is a novel gene implicated in neurodevelopmental disabilities. Am. J. Med. Genet. A 167, 1391–1395 (2015).

    CAS  PubMed  Google Scholar 

  156. 156.

    Simpson, C. L. et al. Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration. Hum. Mol. Genet. 18, 472–481 (2009).

    CAS  PubMed  Google Scholar 

  157. 157.

    Edvardson, S. et al. tRNA N6-adenosine threonylcarbamoyltransferase defect due to KAE1/TCS3 (OSGEP) mutation manifest by neurodegeneration and renal tubulopathy. Eur. J. Hum. Genet. 25, 545–551 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158.

    Braun, D. A. et al. Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly. Nat. Genet. 49, 1529–1538 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. 159.

    Galloway, W. H. & Mowat, A. P. Congenital microcephaly with hiatus hernia and nephrotic syndrome in two sibs. J. Med. Genet. 5, 319–321 (1968).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. 160.

    Abbasi-Moheb, L. et al. Mutations in NSUN2 cause autosomal-recessive intellectual disability. Am. J. Hum. Genet. 90, 847–855 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161.

    Davarniya, B. et al. The role of a novel TRMT1 gene mutation and rare GRM1 gene defect in intellectual disability in two Azeri families. PLoS ONE 10, e0129631 (2015).

    PubMed  PubMed Central  Google Scholar 

  162. 162.

    Freude, K. et al. Mutations in the FTSJ1 gene coding for a novel S-adenosylmethionine-binding protein cause nonsyndromic X-linked mental retardation. Am. J. Hum. Genet. 75, 305–309 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. 163.

    Shaheen, R., Al-Salam, Z., El-Hattab, A. W. & Alkuraya, F. S. The syndrome dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly and lissencephaly (DREAM-PL): report of two additional patients. Am. J. Med. Genet. A 170, 3222–3226 (2016).

    CAS  PubMed  Google Scholar 

  164. 164.

    Alazami, A. M. et al. Mutation in ADAT3, encoding adenosine deaminase acting on transfer RNA, causes intellectual disability and strabismus. J. Med. Genet. 50, 425–430 (2013).

    CAS  PubMed  Google Scholar 

  165. 165.

    Lentini, J. M., Alsaif, H. S., Faqeih, E., Alkuraya, F. S. & Fu, D. DALRD3 encodes a protein mutated in epileptic encephalopathy that targets arginine tRNAs for 3-methylcytosine modification. Nat. Commun. 11, 2510 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166.

    Goodarzi, H. et al. Modulated expression of specific tRNAs drives gene expression and cancer progression. Cell 165, 1416–1427 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Gingold, H. et al. A dual program for translation regulation in cellular proliferation and differentiation. Cell 158, 1281–1292 (2014).

    CAS  PubMed  Google Scholar 

  168. 168.

    Pavon-Eternod, M. et al. tRNA over-expression in breast cancer and functional consequences. Nucleic Acids Res. 37, 7268–7280 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169.

    Santos, M., Fidalgo, A., Varanda, A. S., Oliveira, C. & Santos, M. A. S. tRNA deregulation and its consequences in cancer. Trends Mol. Med. 25, 853–865 (2019).

    CAS  PubMed  Google Scholar 

  170. 170.

    Delaunay, S. & Frye, M. RNA modifications regulating cell fate in cancer. Nat. Cell Biol. 21, 552–559 (2019).

    CAS  PubMed  Google Scholar 

  171. 171.

    Shaheen, R. et al. Mutation in WDR4 impairs tRNA m7G46 methylation and causes a distinct form of microcephalic primordial dwarfism. Genome Biol. 16, 210 (2015).

    PubMed  PubMed Central  Google Scholar 

  172. 172.

    Lin, S. et al. Mettl1/Wdr4-mediated m7G tRNA methylome is required for normal mRNA translation and embryonic stem cell self-renewal and differentiation. Mol. Cell 71, 244–255 e245 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. 173.

    Okamoto, M. et al. tRNA modifying enzymes, NSUN2 and METTL1, determine sensitivity to 5-fluorouracil in HeLa cells. PLoS Genet. 10, e1004639 (2014).

    PubMed  PubMed Central  Google Scholar 

  174. 174.

    Gustavsson, M. & Ronne, H. Evidence that tRNA modifying enzymes are important in vivo targets for 5-fluorouracil in yeast. RNA 14, 666–674 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Blanco, S. et al. Stem cell function and stress response are controlled by protein synthesis. Nature 534, 335–340 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. 176.

    Martinez, F. J. et al. Whole exome sequencing identifies a splicing mutation in NSUN2 as a cause of a Dubowitz-like syndrome. J. Med. Genet. 49, 380–385 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Khan, M. A. et al. Mutation in NSUN2, which encodes an RNA methyltransferase, causes autosomal-recessive intellectual disability. Am. J. Hum. Genet. 90, 856–863 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. 178.

    Blanco, S. et al. Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders. EMBO J. 33, 2020–2039 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. 179.

    Rapino, F. et al. Codon-specific translation reprogramming promotes resistance to targeted therapy. Nature 558, 605–609 (2018).

    CAS  PubMed  Google Scholar 

  180. 180.

    McMahon, M. & Ruggero, D. A wobbly road to drug resistance in melanoma: tRNA-modifying enzymes in translation reprogramming. EMBO J. 37, e99978 (2018).

    PubMed  PubMed Central  Google Scholar 

  181. 181.

    Carlson, B. A. et al. Transfer RNA modification status influences retroviral ribosomal frameshifting. Virology 255, 2–8 (1999).

    CAS  PubMed  Google Scholar 

  182. 182.

    Waas, W. F., Druzina, Z., Hanan, M. & Schimmel, P. Role of a tRNA base modification and its precursors in frameshifting in eukaryotes. J. Biol. Chem. 282, 26026–26034 (2007).

    CAS  PubMed  Google Scholar 

  183. 183.

    Droogmans, L. & Grosjean, H. Enzymatic conversion of guanosine 3’ adjacent to the anticodon of yeast tRNAPhe to N1-methylguanosine and the wye nucleoside: dependence on the anticodon sequence. EMBO J. 6, 477–483 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. 184.

    Noma, A., Kirino, Y., Ikeuchi, Y. & Suzuki, T. Biosynthesis of wybutosine, a hyper-modified nucleoside in eukaryotic phenylalanine tRNA. EMBO J. 25, 2142–2154 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. 185.

    Noma, A. et al. Expanding role of the jumonji C domain as an RNA hydroxylase. J. Biol. Chem. 285, 34503–34507 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. 186.

    Waas, W. F., de Crecy-Lagard, V. & Schimmel, P. Discovery of a gene family critical to wyosine base formation in a subset of phenylalanine-specific transfer RNAs. J. Biol. Chem. 280, 37616–37622 (2005).

    CAS  PubMed  Google Scholar 

  187. 187.

    Grunberger, D., Weinstein, I. B. & Mushinski, J. F. Deficiency of the Y base in a hepatoma phenylalanine tRNA. Nature 253, 66–67 (1975).

    CAS  PubMed  Google Scholar 

  188. 188.

    Kuchino, Y., Borek, E., Grunberger, D., Mushinski, J. F. & Nishimura, S. Changes of post-transcriptional modification of wye base in tumor-specific tRNAPhe. Nucleic Acids Res. 10, 6421–6432 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. 189.

    Rossello-Tortella, M. et al. Epigenetic loss of the transfer RNA-modifying enzyme TYW2 induces ribosome frameshifts in colon cancer. Proc. Natl Acad. Sci. USA 117, 20785–20793 (2020).

    CAS  PubMed  Google Scholar 

  190. 190.

    Hatfield, D. et al. Chromatographic analysis of the aminoacyl-tRNAs which are required for translation of codons at and around the ribosomal frameshift sites of HIV, HTLV-1, and BLV. Virology 173, 736–742 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  191. 191.

    Zhang, H. et al. GSK-3beta-regulated N-acetyltransferase 10 is involved in colorectal cancer invasion. Clin. Cancer Res. 20, 4717–4729 (2014).

    CAS  PubMed  Google Scholar 

  192. 192.

    Shen, Q. et al. NAT10, a nucleolar protein, localizes to the midbody and regulates cytokinesis and acetylation of microtubules. Exp. Cell Res. 315, 1653–1667 (2009).

    CAS  PubMed  Google Scholar 

  193. 193.

    Larrieu, D., Britton, S., Demir, M., Rodriguez, R. & Jackson, S. P. Chemical inhibition of NAT10 corrects defects of laminopathic cells. Science 344, 527–532 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. 194.

    Ito, S. et al. Human NAT10 is an ATP-dependent RNA acetyltransferase responsible for N4-acetylcytidine formation in 18S ribosomal RNA (rRNA). J. Biol. Chem. 289, 35724–35730 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. 195.

    Sharma, S. et al. Yeast Kre33 and human NAT10 are conserved 18S rRNA cytosine acetyltransferases that modify tRNAs assisted by the adaptor Tan1/THUMPD1. Nucleic Acids Res. 43, 2242–2258 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. 196.

    Hicks, D. G. et al. The expression of TRMT2A, a novel cell cycle regulated protein, identifies a subset of breast cancer patients with HER2 over-expression that are at an increased risk of recurrence. BMC Cancer 10, 108 (2010).

    PubMed  PubMed Central  Google Scholar 

  197. 197.

    Fu, D. et al. Human AlkB homolog ABH8 Is a tRNA methyltransferase required for wobble uridine modification and DNA damage survival. Mol. Cell. Biol. 30, 2449–2459 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  198. 198.

    Fu, Y. et al. The AlkB domain of mammalian ABH8 catalyzes hydroxylation of 5-methoxycarbonylmethyluridine at the wobble position of tRNA. Angew. Chem. Int. Ed. Engl. 49, 8885–8888 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. 199.

    Songe-Moller, L. et al. Mammalian ALKBH8 possesses tRNA methyltransferase activity required for the biogenesis of multiple wobble uridine modifications implicated in translational decoding. Mol. Cell. Biol. 30, 1814–1827 (2010).

    PubMed  PubMed Central  Google Scholar 

  200. 200.

    Shimada, K. et al. A novel human AlkB homologue, ALKBH8, contributes to human bladder cancer progression. Cancer Res. 69, 3157–3164 (2009).

    CAS  PubMed  Google Scholar 

  201. 201.

    Monies, D., Vagbo, C. B., Al-Owain, M., Alhomaidi, S. & Alkuraya, F. S. Recessive truncating mutations in ALKBH8 cause intellectual disability and severe impairment of wobble uridine modification. Am. J. Hum. Genet. 104, 1202–1209 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. 202.

    Steinthorsdottir, V. et al. A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat. Genet. 39, 770–775 (2007).

    CAS  PubMed  Google Scholar 

  203. 203.

    Arragain, S. et al. Identification of eukaryotic and prokaryotic methylthiotransferase for biosynthesis of 2-methylthio-N6-threonylcarbamoyladenosine in tRNA. J. Biol. Chem. 285, 28425–28433 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. 204.

    Wei, F. Y. et al. Deficit of tRNALys modification by Cdkal1 causes the development of type 2 diabetes in mice. J. Clin. Invest. 121, 3598–3608 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. 205.

    Santos, M. et al. Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification. Nat. Commun. 11, 296 (2020).

    PubMed  PubMed Central  Google Scholar 

  206. 206.

    Suzuki, T., Ikeuchi, Y., Noma, A., Suzuki, T. & Sakaguchi, Y. Mass spectrometric identification and characterization of RNA-modifying enzymes. Methods Enzymol. 425, 211–229 (2007).

    CAS  PubMed  Google Scholar 

  207. 207.

    Su, D. et al. Quantitative analysis of ribonucleoside modifications in tRNA by HPLC-coupled mass spectrometry. Nat. Protoc. 9, 828–841 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. 208.

    Ross, R. L., Cao, X. & Limbach, P. A. Mapping post-transcriptional modifications onto transfer ribonucleic acid sequences by liquid chromatography tandem mass spectrometry. Biomolecules 7, 21 (2017).

    PubMed Central  Google Scholar 

  209. 209.

    Pomerantz, S. C. & McCloskey, J. A. Analysis of RNA hydrolyzates by liquid chromatography-mass spectrometry. Methods Enzymol. 193, 796–824 (1990).

    CAS  PubMed  Google Scholar 

  210. 210.

    Sakaguchi, Y., Miyauchi, K., Kang, B. I. & Suzuki, T. Nucleoside analysis by hydrophilic interaction liquid chromatography coupled with mass spectrometry. Methods Enzymol. 560, 19–28 (2015).

    CAS  PubMed  Google Scholar 

  211. 211.

    Heiss, M., Reichle, V. F. & Kellner, S. Observing the fate of tRNA and its modifications by nucleic acid isotope labeling mass spectrometry: NAIL-MS. RNA Biol. 14, 1260–1268 (2017).

    PubMed  PubMed Central  Google Scholar 

  212. 212.

    Ohira, T. & Suzuki, T. Precursors of tRNAs are stabilized by methylguanosine cap structures. Nat. Chem. Biol. 12, 648–655 (2016).

    CAS  PubMed  Google Scholar 

  213. 213.

    Garalde, D. R. et al. Highly parallel direct RNA sequencing on an array of nanopores. Nat. Methods 15, 201–206 (2018).

    CAS  PubMed  Google Scholar 

  214. 214.

    Kim, D. et al. The architecture of SARS-CoV-2 transcriptome. Cell 181, 914–921 e910 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. 215.

    Smith, A. M., Jain, M., Mulroney, L., Garalde, D. R. & Akeson, M. Reading canonical and modified nucleobases in 16S ribosomal RNA using nanopore native RNA sequencing. PLoS ONE 14, e0216709 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. 216.

    Liu, H. et al. Accurate detection of m6A RNA modifications in native RNA sequences. Nat. Commun. 10, 4079 (2019).

    PubMed  PubMed Central  Google Scholar 

  217. 217.

    Workman, R. E. et al. Nanopore native RNA sequencing of a human poly(A) transcriptome. Nat. Methods 16, 1297–1305 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. 218.

    Guzzi, N. et al. Pseudouridylation of tRNA-derived fragments steers translational control in stem cells. Cell 173, 1204–1216 e1226 (2018).

    CAS  PubMed  Google Scholar 

  219. 219.

    Yarham, J. W. et al. Defective i6A37 modification of mitochondrial and cytosolic tRNAs results from pathogenic mutations in TRIT1 and its substrate tRNA. PLoS Genet. 10, e1004424 (2014).

    PubMed  PubMed Central  Google Scholar 

  220. 220.

    Powell, C. A. et al. TRMT5 mutations cause a defect in post-transcriptional modification of mitochondrial tRNA associated with multiple respiratory-chain deficiencies. Am. J. Hum. Genet. 97, 319–328 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. 221.

    Igoillo-Esteve, M. et al. tRNA methyltransferase homolog gene TRMT10A mutation in young onset diabetes and primary microcephaly in humans. PLoS Genet. 9, e1003888 (2013).

    PubMed  PubMed Central  Google Scholar 

  222. 222.

    Vilardo, E. & Rossmanith, W. Molecular insights into HSD10 disease: impact of SDR5C1 mutations on the human mitochondrial RNase P complex. Nucleic Acids Res. 43, 5112–5119 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  223. 223.

    Chen, J. & Patton, J. R. Pseudouridine synthase 3 from mouse modifies the anticodon loop of tRNA. Biochemistry 39, 12723–12730 (2000).

    CAS  PubMed  Google Scholar 

  224. 224.

    Lecointe, F. et al. Characterization of yeast protein Deg1 as pseudouridine synthase (Pus3) catalyzing the formation of psi 38 and psi 39 in tRNA anticodon loop. J. Biol. Chem. 273, 1316–1323 (1998).

    CAS  PubMed  Google Scholar 

  225. 225.

    Shaheen, R. et al. A homozygous truncating mutation in PUS3 expands the role of tRNA modification in normal cognition. Hum. Genet. 135, 707–713 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. 226.

    de Brouwer, A. P. M. et al. Variants in PUS7 cause intellectual disability with speech delay, microcephaly, short stature, and aggressive behavior. Am. J. Hum. Genet. 103, 1045–1052 (2018).

    PubMed  PubMed Central  Google Scholar 

  227. 227.

    Arrondel, C. et al. Defects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome. Nat. Commun. 10, 3967 (2019).

    PubMed  PubMed Central  Google Scholar 

  228. 228.

    Rodriguez, V. et al. Chromosome 8 BAC array comparative genomic hybridization and expression analysis identify amplification and overexpression of TRMT12 in breast cancer. Genes Chromosomes Cancer 46, 694–707 (2007).

    CAS  PubMed  Google Scholar 

  229. 229.

    Rodriguez, V. et al. Structure-function analysis of human TYW2 enzyme required for the biosynthesis of a highly modified wybutosine (yW) base in phenylalanine-tRNA. PLoS ONE 7, e39297 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. 230.

    de Crecy-Lagard, V. et al. Matching tRNA modifications in humans to their known and predicted enzymes. Nucleic Acids Res. 47, 2143–2159 (2019).

    PubMed  PubMed Central  Google Scholar 

  231. 231.

    Miyauchi, K., Ohara, T. & Suzuki, T. Automated parallel isolation of multiple species of non-coding RNAs by the reciprocal circulating chromatography method. Nucleic Acids Res. 35, e24 (2007).

    PubMed  PubMed Central  Google Scholar 

  232. 232.

    Suzuki, T. & Suzuki, T. Chaplet column chromatography: isolation of a large set of individual RNAs in a single step. Methods Enzymol. 425, 231–239 (2007).

    CAS  PubMed  Google Scholar 

  233. 233.

    Nagao, A. et al. Hydroxylation of a conserved tRNA modification establishes non-universal genetic code in echinoderm mitochondria. Nat. Struct. Mol. Biol. 24, 778–782 (2017).

    CAS  PubMed  Google Scholar 

  234. 234.

    Krog, J. S. et al. 3-(3-amino-3-carboxypropyl)-5,6-dihydrouridine is one of two novel post-transcriptional modifications in tRNALys(UUU) from Trypanosoma brucei. FEBS J. 278, 4782–4796 (2011).

    CAS  PubMed  Google Scholar 

  235. 235.

    Miyauchi, K., Kimura, S. & Suzuki, T. A cyclic form of N6-threonylcarbamoyladenosine as a widely distributed tRNA hypermodification. Nat. Chem. Biol. 9, 105–111 (2013).

    CAS  PubMed  Google Scholar 

  236. 236.

    Matuszewski, M. et al. A hydantoin isoform of cyclic N6-threonylcarbamoyladenosine (ct6A) is present in tRNAs. Nucleic Acids Res. 45, 2137–2149 (2017).

    CAS  PubMed  Google Scholar 

  237. 237.

    Kang, B. I. et al. Identification of 2-methylthio cyclic N6-threonylcarbamoyladenosine (ms2ct6A) as a novel RNA modification at position 37 of tRNAs. Nucleic Acids Res. 45, 2124–2136 (2017).

    CAS  PubMed  Google Scholar 

  238. 238.

    Salazar, J. C., Ambrogelly, A., Crain, P. F., McCloskey, J. A. & Soll, D. A truncated aminoacyl-tRNA synthetase modifies RNA. Proc. Natl Acad. Sci. USA 101, 7536–7541 (2004).

    CAS  PubMed  Google Scholar 

  239. 239.

    Ikeuchi, Y. et al. Agmatine-conjugated cytidine in a tRNA anticodon is essential for AUA decoding in archaea. Nat. Chem. Biol. 6, 277–282 (2010).

    CAS  PubMed  Google Scholar 

  240. 240.

    Mandal, D. et al. Agmatidine, a modified cytidine in the anticodon of archaeal tRNAIle, base pairs with adenosine but not with guanosine. Proc. Natl Acad. Sci. USA 107, 2872–2877 (2010).

    CAS  PubMed  Google Scholar 

  241. 241.

    Mandal, D. et al. Identification and codon reading properties of 5-cyanomethyl uridine, a new modified nucleoside found in the anticodon wobble position of mutant haloarchaeal isoleucine tRNAs. RNA 20, 177–188 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  242. 242.

    Rose, S. et al. The hyperthermophilic partners Nanoarchaeum and Ignicoccus stabilize their tRNA T-loops via different but structurally equivalent modifications. Nucleic Acids Res. 48, 6906–6918 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  243. 243.

    Sakai, Y., Miyauchi, K., Kimura, S. & Suzuki, T. Biogenesis and growth phase-dependent alteration of 5-methoxycarbonylmethoxyuridine in tRNA anticodons. Nucleic Acids Res. 44, 509–523 (2016).

    CAS  PubMed  Google Scholar 

  244. 244.

    Chen, P., Crain, P. F., Nasvall, S. J., Pomerantz, S. C. & Bjork, G. R. A “gain of function” mutation in a protein mediates production of novel modified nucleosides. EMBO J. 24, 1842–1851 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  245. 245.

    Dumelin, C. E., Chen, Y., Leconte, A. M., Chen, Y. G. & Liu, D. R. Discovery and biological characterization of geranylated RNA in bacteria. Nat. Chem. Biol. 8, 913–919 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  246. 246.

    Dal Magro, C. et al. A vastly increased chemical variety of RNA modifications containing a thioacetal structure. Angew. Chem. Int. Ed. 57, 7893–7897 (2018).

    CAS  Google Scholar 

  247. 247.

    Jager, G., Chen, P. & Bjork, G. R. Transfer RNA bound to MnmH protein is enriched with geranylated tRNA–a possible intermediate in its selenation? PLoS ONE 11, e0153488 (2016).

    PubMed  PubMed Central  Google Scholar 

  248. 248.

    Sierant, M. et al. Escherichia coli tRNA 2-selenouridine synthase (SelU) converts S2U-RNA to Se2U-RNA via S-geranylated-intermediate. FEBS Lett. 592, 2248–2258 (2018).

    CAS  PubMed  Google Scholar 

  249. 249.

    Reichle, V. F., Petrov, D. P., Weber, V., Jung, K. & Kellner, S. NAIL-MS reveals the repair of 2-methylthiocytidine by AlkB in E. coli. Nat. Commun. 10, 5600 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The author is grateful to members of his laboratory, in particular K. Miyauchi, T. Ohira and K. Minowa, for preparing tables and figures and for providing valuable suggestions. This work was supported by Grants-in-Aid for Scientific Research (18H05272) from JSPS, and Exploratory Research for Advanced Technology (ERATO; JPMJER2002) from JST. The author apologizes to those of his colleagues whose many contributions related to tRNA modifications could not be cited in this Review owing to space limitations.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Tsutomu Suzuki.

Ethics declarations

Competing interests

The author declares no competing interests.

Additional information

Peer review information

Nature Reviews Molecular Cell Biology thanks Juan Alfonzo, Tao Pan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Anticodon

A unit of three nucleotides at positions 34–36 in transfer RNA, which corresponds with three nucleotides of an mRNA codon.

Reading frame maintenance

Of the three possible mRNA reading frames, only one reading frame generates the correct amino acid sequence. Transfer RNA modification in the anticodon is crucial for maintaining the correct reading frame.

Acceptor stem

A stem structure made of seven base pairs formed by the 5′ and 3′ ends of transfer RNA. The 3′ CCA sequence and the discriminator base protrude from this stem.

Discriminator base

The fourth nucleotide (position 73) from the 3′ end of transfer RNA (tRNA); frequently recognized by aminoacyl-tRNA synthetases and is a determinant of aminoacylation.

Family box

In the genetic code, a codon box in which four codons are synonymous (encode the same amino acid).

Two-codon sets

In the genetic code, a codon set in which two codons ending in pyrimidines or in purines are synonymous (specifying the same amino acid).

Ribose puckering

A low-strain conformation of the ribose sugar ring in which atoms in the ring are displaced from the plane.

C3′ endo form

Major puckering of ribose found in A-form duplex of RNA.

Rapid tRNA decay

A pathway of 5′–3′ exonucleolytic degradation of mature transfer RNAs (tRNAs) that lack certain modifications.

Warburg effect

Refers to tumours that metabolize glucose anaerobically rather than aerobically even when oxygen is available.

Elongator complex

A transfer RNA-modifying enzyme complex catalysing 5-methoxyarbonylmethyluridine (mcm5U) formation.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Suzuki, T. The expanding world of tRNA modifications and their disease relevance. Nat Rev Mol Cell Biol 22, 375–392 (2021). https://doi.org/10.1038/s41580-021-00342-0

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing