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  • Review Article
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tRNA dysregulation and disease

Nature Reviews Genetics volume 23, pages 651–664 (2022)Cite this article

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Abstract

tRNAs are key adaptor molecules that decipher the genetic code during translation of mRNAs in protein synthesis. In contrast to the traditional view of tRNAs as ubiquitously expressed housekeeping molecules, awareness is now growing that tRNA-encoding genes display tissue-specific and cell type-specific patterns of expression, and that tRNA gene expression and function are both dynamically regulated by post-transcriptional RNA modifications. Moreover, dysregulation of tRNAs, mediated by alterations in either their abundance or function, can have deleterious consequences that contribute to several distinct human diseases, including neurological disorders and cancer. Accumulating evidence shows that reprogramming of mRNA translation through altered tRNA activity can drive pathological processes in a codon-dependent manner. This Review considers the emerging evidence in support of the precise control of functional tRNA levels as an important regulatory mechanism that coordinates mRNA translation and protein expression in physiological cell homeostasis, and highlights key examples of human diseases that are linked directly to tRNA dysregulation.

Key points

  • tRNA-encoding genes display tissue-specific and cell type-specific patterns of expression.

  • tRNA gene expression and function are both dynamically regulated by post-transcriptional RNA modifications.

  • Dysregulation of tRNAs, mediated by alterations in either their abundance or function, can have deleterious consequences that contribute to several distinct human diseases.

  • Reprogramming of mRNA translation through altered tRNA activity can drive pathological processes in a codon-dependent manner.

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Fig. 1: tRNA molecular structure and variance in isodecoder prevalence in eukaryotic species.
Fig. 2: RNA polymerase III involvement in disease.
Fig. 3: Epigenetic mechanisms and sequence variability might influence nuclear tRNA expression.
Fig. 4: tRNA maturation and splicing defects in disease.
Fig. 5: Defects in tRNA modifications or aminoacylation influence translation.
Fig. 6: Alterations in the tRNA pool can drive disease and offer avenues for therapeutic intervention.

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Acknowledgements

E.A.O. is supported by the Pew Latin American Fellows Program in the Biomedical Sciences from Pew Charitable Trusts and by a fellowship from the Damon Runyon Cancer Research Foundation (DRG-2378–19). R.I.G. is supported by an Outstanding Investigator Award (R35CA232115) from the National Cancer Institute (NCI) of the National Institutes of Health (NIH).

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Authors and Affiliations

  1. Stem Cell Program, Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA

    Esteban A. Orellana, Elisabeth Siegal & Richard I. Gregory

  2. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA

    Esteban A. Orellana & Richard I. Gregory

  3. Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA

    Richard I. Gregory

  4. Harvard Initiative for RNA Medicine, Harvard University, Boston, MA, USA

    Richard I. Gregory

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  1. Esteban A. Orellana
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The authors contributed equally to all aspects of the article.

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Correspondence to Richard I. Gregory.

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R.I.G. is a co-founder and scientific advisory board member of 28/7 Therapeutics and Theonys Therapeutics. The other authors declare no competing interests.

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Nature Reviews Genetics thanks Valérie de Crécy-Lagard, Jeff Coller and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Orellana, E.A., Siegal, E. & Gregory, R.I. tRNA dysregulation and disease. Nat Rev Genet 23, 651–664 (2022). https://doi.org/10.1038/s41576-022-00501-9

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