The problem of genetic code misreading during protein synthesis

Abstract

Saccharomyces cerevisiae has been an important model for determining the frequency of translational misreading events, those in which a tRNA pairs incorrectly to the mRNA and inserts an amino acid not specified by the codon in the mRNA. Misreading errors have been quantified in vivo using reporter protein systems or mass spectrometry with both approaches converging on a simple model for most misreading. The available data show that misreading tRNAs must form stereotypical base mismatches that correspond to those that can mimic Watson–Crick base pairs when formed in the ribosomal A site. Errors involving other mismatches occur significantly less frequently. This work debunks the idea of an average misreading frequency of 5 × 10−4 per codon that extends across the genetic code. Instead, errors come in two distinct classes—high frequency and low frequency events—with most errors being of the low frequency type. A comparison of misreading errors in S. cerevisiae and Escherichia coli suggests the existence of a mechanism that reduces misreading frequency in yeast; this mechanism may operate in eukaryotes generally.

The amino acid substitution affects cellular response to mistranslation

“…Mistranslation, the incorporation of an amino acid not specified by the “standard” genetic code, occurs with frequencies varying from 10 −2 to 10 −5 , depending on the codon (reviewed in Joshi et al 2019). Mistranslation increases in specific environmental conditions [reviewed in Mohler and Ibba (2017)] and due to mutations in the translation machinery, including in tRNA encoding genes [reviewed in Berg and Brandl (2020)].…”

Translational recoding: canonical translation mechanisms reinterpreted

“…Failing to discriminate against incorrect aa-tRNA results in missense errors of translation. Generally, the fidelity of decoding is very high, with a frequency of missense errors in the range from <10 −7 to 10 −4 per codon depending on the type of mismatch and the position of the amino acid in the protein (1)(2)(3)(4). At the end of the open reading frame, stop codons (UAA, UAG and UGA) are recognized by termination (release) factors (RF1 and RF2 in bacteria or eRF1 in eukaryotes).…”

Evolution of ribosomal protein network architectures

“…rRNA and r-protein networks may have also co-evolved for optimizing not only assembly processes but also r-protein synthesis 46 . The expansion of network connectivity indeed follows the increasing accuracy and complexity of the ribosome's tasks from prokaryotes to eukaryotes 27,29 . The burst of LSU connectivity parallels its gradual specialization in regulating multiple sub-functions that co-emerged with the growth of cellular complexity.…”