Ribosomal frameshifting and transcriptional slippage: From genetic steganography and cryptography to adventitious use

Atkins, John F.; Loughran, Gary; Bhatt, Pramod R.; Firth, Andrew E.; Baranov, Pavel V.

Translation of a short upstream ORF (uORF/leader ORF) which depends on the physiological state of the cell, can influence expression of its downstream 'main' gene. uORF translation can in effect be a sensor for exogenous factors, such as the presence and concentration of specific metabolites. Though macrolide antibiotics inhibit bacterial translation, bacteria have developed uORF translational systems for sensing very low levels of their presence and activating initiation of synthesis of a resistance determinant. uORFmediated regulation of ermC that renders bacteria resistant to erythromycin and other macrolide antibiotics has been particularly well-studied in part because of the clinical importance of macrolides. The most recent generation of macrolides are ketolides, e.g. telithromycin. While some macrolides cause stalling during uORF translation with resulting prevention of sequestration of the ermC initiator, telithromycin instead, in a manner largely independent of nascent peptide sequence, induces a proportion of ribosomes to shift frame. Their continued translation in the new frame into the intergenic spacer unfolds mRNA structure and permits initiation of ermC expression (61) . Prior to this discovery, the most promising candidate for productive utilization of frameshifting to influence downstream expression via mRNA unfolding had been pheL, the uORF for the downstream bacterial phenylalanine biosynthesis gene, pheA, (especially Enterobacteria, e.g. E. coli). However, the frameshifting that does occur seems to be a by-product of the features responsible for the transcription attenuation control mechanism utilized and to be incidental (19) .