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.

With the exception of specialized cases such as Euplotes and S. cerevisiae Ty1/antizyme-like +1 frameshifting, all high level frameshing including much productively utilized frameshifting, involves stimulatory elements that enhance the proportion of ribosomes that shift frame at the shift site. Stimulators can act singly or in combination with other recoding signals whose effects are either inhibitory or stimulatory on their own with structural transitions and the degree of spacing of oncoming ribosomes being important in several cases. They can act synergistically as illustrated by IS911 where one of the stimulators also serves a role independent of frameshifting (194) . Stimulators can act in a variety of ways involving (i) certain interactions of the newly synthesized nascent protein chain with the ribosome peptide exit tunnel on its way to the exterior of the ribosome, (ii) pairing of the mRNA with rRNA close to the mRNA exit path, (iii) mRNA structure 5 of the recoding site stimulating bypassing and perhaps also being able to stimulate at least +1 frameshifting, (iv) likely mRNA pairing with rRNA close to the mRNA entrance channel, and (v) intra-mRNA structure 3 of the shift site. trans-acting factors include polyamines, protein release factor competing for the A-site, protein binding to a 3 mRNA sequence and miRNA. While codon usage (456) and pause sites further upstream could influence ribosome 'traffic' spacing and so potentally frameshifting efficiency, this has been established for initiation rate. HIV encoded Tat interaction with Tar in the 5 UTR can influence initiation frequency with substantial consequences for downstream frameshifting efficiency (457) , though the existence of a relevant IRES in the 5 UTR has been challenged (458) .