Hydroxylation and translational adaptation to stress: some answers lie beyond the STOP codon

Abstract

Regulation of protein synthesis contributes to maintenance of homeostasis and adaptation to environmental changes. mRNA translation is controlled at various levels including initiation, elongation and termination, through post-transcriptional/translational modifications of components of the protein synthesis machinery. Recently, protein and RNA hydroxylation have emerged as important enzymatic modifications of tRNAs, elongation and termination factors, as well as ribosomal proteins. These modifications enable a correct STOP codon recognition, ensuring translational fidelity. Recent studies are starting to show that STOP codon read-through is related to the ability of the cell to cope with different types of stress, such as oxidative and chemical insults, while correlations between defects in hydroxylation of protein synthesis components and STOP codon read-through are beginning to emerge. In this review we will discuss our current knowledge of protein synthesis regulation through hydroxylation of components of the translation machinery, with special focus on STOP codon recognition. We speculate on the possibility that programmed STOP codon read-through, modulated by hydroxylation of components of the protein synthesis machinery, is part of a concerted cellular response to stress.

Keywords: Dioxygenases; Post-translational modifications; Protein synthesis; Translational fidelity.

Fig. 1

Hydroxylation-dependent translation regulation. The diagram shows how hydroxylases may exert translational control through hydroxylation of different components of the translation machinery. Ribosomal proteins are direct targets of hydroxylases both in the large subunit (RPL16, RPL8 and RPL27) and in the small subunit (RPS23). Some tRNAs (like tRNA^PHE or tRNA^GLY) are also subjected to hydroxylation as part of the post-transcriptional modifications that alter their interactions with the ribosome and mRNAs. Control of translation may also be exerted through regulation of translation factors. Both elongation factors (EF-Tu and EF-P), as well as termination factors (eRF1) have been reported to be hydroxylated

Fig. 2

STOP codon read-through. High translation fidelity ensures STOP codon recognition as such by the release factor complex according to the canonical termination mechanism (left). However, non Watson–Crick base pairing between the UAG codon and a tRNA containing a near cognate anticodon could lead to the incorporation of a new amino acid (green) instead of translation termination, allowing for the synthesis of longer polypeptides containing a C-terminal extension (right). This phenomenon known as STOP codon read-through, although infrequent, occurs at basal levels under normal conditions, and several works point to the possibility that it could be a physiological mechanism of translation regulation. Ongoing research is focused on the elucidation of the impact that the incorporation of C-terminal additional domains by STOP codon read-through could have on cell physiology

Fig. 3

Possible regulation of the stress response by STOP codon read-through coupled to sensing of environmental conditions. STOP codon read-through is induced in stress conditions, and confers stress resistance to the cell. Stress conditions might be sensed in part by 2OG-dependent oxygenases involved in regulation of translation fidelity (dotted line). Although available evidence is compatible with this model, further research is required to elucidate the molecular details of this possible control circuit