Fig 1.
tRNA decoder regulates error ratio in translation decoding.
In physiological conditions, errors in mRNA translation may occur but are generally well tolerated. However, the frequency of errors is dramatically increased in response to stresses. When amino acid misincorporation reaches intolerable levels, this contributes to dysfunction of cellular physiology and may cause pathogenesis. In general, the error ratio in translation decoding primarily depends on tRNA wobbling (cognate) and misdecoding (noncognate) as well as misacylation of tRNAs. aa, amino acid; iMet-tRNA, initiator tRNA Methionine; tRNA, transfer RNA.
Table 1.
The types and outcome of errors in translation machinery.
Fig 2.
tRNA wobbling increases the risk of mistranslation.
In the central dogma, DNA transcribes RNA and RNA translates protein. In the human mutation database, the major (57%) mutation types are missense/nonsense (the right panel) that reflect the consequence of DNA errors at genomic level. Ribosome, as the translation machinery, essentially transduces genetic code to functional protein performed by aa-tRNAs. In human genome, 15 out of 64 tRNA types are actually missing partially because of low confidence (score < 50), including eight tRNAANN and seven tRNAGNN. Because of these missing tRNAs and the expanding wobble rules, the mRNA codon can be decoded by cognate or noncognate tRNAs, leading to modulation of translation efficiency and misincorporation (the left panel). At the bottom, the revised wobble rules and the consequent wobble types are listed according to the wobble position 3 of triplet codon. As for eight tRNAANN, NNU codons will be decoded by NNG or NNU anticodon of tRNAs. As for seven tRNAGNN, NNC codons will be decoded by NNA(I) or NNU anticodon of tRNAs. For specific missing tRNAs, the consequent wobble (tRNA wobbling or misdecoding) are detailed in Fig 3. aa-tRNA, aminoacyl-tRNA; tRNA, transfer RNA.
Fig 3.
Errors in translation decoding are regulated by tRNA wobbling at all three codon positions.
Sixty-four tRNA sets are summarized and specified in parallel with codon degeneracy (left bottom and central). Faithful or misincorporated protein can result from decoding by cognate or near-cognate tRNA at position 3. For eight missing tRNAANN (yellow text), NNU•tRNAUNN wobble-dependent misdecoding by near-cognate tRNAs mainly occurs at the two box (I–VI) and six box tRNA sets (arginine-serine misincorporation) (VII). For seven missing tRNAGNN (red text), NNC codons will be decoded by cognate tRNAs without amino acid misincorporation (VIII) because they happen at the four and six box tRNA sets. Since leucine and phenylalanine share UUN codon, leucine-phenylalanine misincorporation may occur across the six and two box tRNA sets. Besides wobbling at position 3, mRNA codons can be falsely decoded by “far-cognate” tRNA at position 1 and 2 (in the text). Missing tRNAs are indicated as question mark. Individual wobble and misdecoding are labeled as green and red text, respectively. tRNA, transfer RNA.
Table 2.
Revised wobble rules.
Fig 4.
Fidelity and errors of translation decoding and the implications in viral evolution and cancer development.
(a) aa-tRNAs are synthesized by sampling from the amino acid pool and tRNA pool and require catalysis by aaRSs. This process may accidently introduce misacylated aa-tRNAs, because the types of tRNAs and amino acids are difficult to be distinguished by involved aminoacyl synthetase because of analogous structures. (b) During elongation, tRNA wobbling will increase translation efficiency. Misincorporation can also be introduced because of tRNA misdecoding (amino acid misincorporation caused by excessive wobble decoding), especially when certain codon-paired tRNA species are missing. Finally, the fidelity of translation machinery will be impaired and produce mutated proteome, including RNA and DNA polymerases, aaRSs, and accessories. (c) Mistranslation of RdRP in RNA viruses will augment generation of a mutated virome (quasispecies) and facilitate viral evolution and adaption. (d) Similarly, mistranslation of cellular DNA replication-related enzymes and relative proteins amplifies mutagenesis in the genome and contributes to cancer development. aaRS, aminoacyl-tRNA synthetase; aa-tRNA, aminoacyl-tRNA; RdRP, RNA-dependent RNA polymerase; tRNA, transfer RNA.