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Emerging roles of tRNA in adaptive translation, signalling dynamics and disease
Nature Reviews Geneticsvolume 16, pages98–112 (2015)Cite this article
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Key Points
tRNAs are key molecules for translation that deliver amino acids to the ribosome to translate genetic information in an mRNA template-directed manner. However, emerging evidence suggests that tRNAs have a more central role in a stress response paradigm by functioning directly as signalling molecules in adaptive translation.
tRNA composition differs markedly in various cells and tissues to meet diverse translational demands. The expression and abundance of tRNA pools are shaped by tissue-specific chromatin accessibility and RNA polymerase III interactions.
Stress-related tRNA functions operate on different timescales and include reprogramming covalent modifications to modulate decoding fidelity, fragmentation in the anticodon loop to interfere with translation initiation, and global tRNA depletion by deactivation of the ubiquitous CCA termini.
Mutations in tRNAs and in tRNA processing or modifying genes are linked to several human diseases, with some tissues affected more than others. Mitochondria generally carry a single copy of each tRNA-encoding gene and are particularly vulnerable to deleterious mutations.
Many human diseases (for example, cancer-related and neurodegenerative pathologies) do not have a direct mutational link to tRNAs but alter tRNA pools as a secondary effect of the disease biology.
A complete inventory of the tRNA pool (and tRNA fragments) in each tissue is necessary to understand tissue-specific features that modulate pathology.
Abstract
tRNAs, nexus molecules between mRNAs and proteins, have a central role in translation. Recent discoveries have revealed unprecedented complexity of tRNA biosynthesis, modification patterns, regulation and function. In this Review, we present emerging concepts regarding how tRNA abundance is dynamically regulated and how tRNAs (and their nucleolytic fragments) are centrally involved in stress signalling and adaptive translation, operating across a wide range of timescales. Mutations in tRNAs or in genes affecting tRNA biogenesis are also linked to complex human diseases with surprising heterogeneity in tissue vulnerability, and we highlight cell-specific aspects that modulate the disease penetrance of tRNA-based pathologies.
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Acknowledgements
The authors acknowledge careful reading of the manuscript and numerous suggestions by R. Smock and laboratory members. Work in the authors' laboratory on tRNA and translation is supported by grants from Deutsche Forschungsgemeinschaft, German Federal Ministry of Education and Research, and Marie–Curie Training Network of the European Union.
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Sebastian Kirchner
Present address: Present address: Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, 120 University Place, Glasgow G12 8TA, UK.,
Zoya Ignatova
Present address: Present address: Institute of Biochemistry and Molecular Biology, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany.,
Authors and Affiliations
Institute of Biochemistry and Biology, University of Potsdam, Karl-Liebknecht-Strasse 24–25, Potsdam, 14476, Germany
Sebastian Kirchner & Zoya Ignatova
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Correspondence toZoya Ignatova.
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Glossary
- Anticodon
Nucleotides 34, 35 and 36 of each tRNA that recognize a specific codon of mRNA.
- A-site
The site of entry of the aminoacyl tRNA in the ribosome.
- Codon
Three consecutive nucleotides on mRNA that encode one amino acid.
- Translational frameshifting
A shift in the linear readthrough of mRNA in which the ribosome reads the second or the third nucleotide of a codon as the first nucleotide.
- Wobbling
Non-Watson–Crick base pairing between the third base in the codon with the first nucleotide of the tRNA anticodon (nucleotide 34 in tRNA numbering).
- tRNA isoacceptors
Different tRNA species carrying the same amino acids but with different anticodon sequences.
- tRNA isodecoders
Distinct tRNA species bearing the same amino acids and anticodons but with sequence variations in the tRNA body.
- Transcription factors
Proteins that bind to specific sequences in DNA and control the transcription of a gene.
- Synonymous substitutions
Substitutions of nucleotides in the exons of protein-coding genes that do not change the encoded amino acid.
- Codon bias
The difference in occurrence of codons encoding the same amino acid.
- Paralogous genes
Genes that arose from a duplication event but have diverged from a parent copy by mutation and selection drift; they may evolve new functions.
- Proteotoxic stress
A collective term to describe the intracellular stress caused by toxic protein aggregation.
- tRNA isoacceptor family
A family of all tRNA isoacceptors carrying the same amino acid.
- Endonuclease
An enzyme that hydrolyses the phosphodiester bond between two nucleotides in a sequence.
- RNA interference
A process by which short RNA sequences block gene expression by binding to specific mRNAs to cause their destruction.
- Homoplasmy
The presence of a single mitochondrial-encoded tDNA genotype in a cell.
- Heteroplasmy
The presence of a mixture of more than one mitochondrial-encoded tDNA genotype in a cell.
- tRNAome
The collective definition of the entire set of tRNAs expressed in a cell, a tissue or an organism at a given time.
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Kirchner, S., Ignatova, Z. Emerging roles of tRNA in adaptive translation, signalling dynamics and disease.Nat Rev Genet16, 98–112 (2015). https://doi.org/10.1038/nrg3861
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