Post-transcriptional modification to the core of tRNAs modulates translational misreading errors

Abstract

Protein synthesis on the ribosome involves the successive rapid recruitment of cognate aminoacyl-tRNAs and rejection the much more numerous incorrect near or non-cognates. The principal feature of translation elongation is that at every step many incorrect aa-tRNAs unsuccessfully enter the A site for each cognate accepted. Normal levels of translational accuracy require that cognate tRNAs have relatively similar rates of acceptance by the ribosome. To achieve that, tRNAs evolved to compensate for differences in amino acid properties and codon-anticodon strength. Part of that response involved tRNA post-transcriptional modifications, which can affect decoding efficiency, accuracy and structural stability of the tRNAs. The most intensively modified regions of the tRNA are the anticodon loop and structural core of the tRNA. Anticodon loop modifications directly affect codon-anticodon pairing and therefore modulate accuracy. Core modifications have been thought to ensure consistent decoding rates principally by stabilizing tRNA structure to avoid degradation, however degradation due to instability appears to only be a significant issue above normal growth temperatures. We suspected that the greater role of modification at normal temperatures might be to tune tRNAs to maintain consistent intrinsic rates of acceptance and peptide transfer and that hypomodification by altering these rates might degrade the process of discrimination, leading to increased translational errors. Here we present evidence that most tRNA core modifications do modulate the frequency of misreading errors suggesting that the need to maintain accuracy explains their deep evolutionary conservation.