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.
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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.
The author declares no competing interests.
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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.
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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