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.

Many other viral genera also utilize −1 frameshifting in synthesis of their replicase (Table 1 ). An example being members of the Astroviridae family which, like members of the Caliciviridae and Picornaviridae, have non-segmented, single-stranded, positive-sense RNA genomes (111, 112) . In humans, they are important causes of childhood gastroenteritis. Others use +1 or −2 frameshifting for the same purpose, e.g. Leishmania virus 1, and Trichomonas vaginalis virus 1 (family Totiviridae, with other members of the same family using −1 frameshifting or reinitiation to express polymerase). As the efficiency of this +1 frameshifting can be low, its experimental analysis is sometimes difficult. Curiously, different members of the family Closteroviridae, plant viruses with among the largest RNA genomes, appear to use shifting to the +1 frame at different distances from the terminator, to synthesize their RNA dependent RNA polymerase but further work is needed (113, 114) and contrast in (115) . In cardioviruses, the polymerase is encoded in-frame with upstream structural protein coding sequence, and frameshifting is utilized to divert excess ribosomes from decoding polymerase. This is illustrated by encephalomyocarditis virus (EMCV) whose small positive-sense singlestranded RNA was widely used as a model mRNA in early eukaryotic cell-free protein synthesis studies. Its −1 frameshifting mediates synthesis of a functionally important protein that has just 11 or 12 N-terminal amino acids encoded by the zero frame and 117 amino acids encoded from the new frame 'internal' ORF (58) ( Figure 3B ). For the related Theiler's murine encephalomyelitis virus, the trans-frame encoded protein is just 14 amino acids, 6 encoded by the zero frame and 8 by the new frame (58, 59) . Its frameshifting is a remarkable 74-82% efficient. It serves to divert most ribosomes to termination and allow only a greatly reduced number to continue for downstream encoded protein synthesis (a ribosome 'sink' function for frameshifting) (59) . Such a 'sink' function may be ances-tral in EMCV progenitors to the product of new frame translation acquiring a function. Interestingly, cardiovirus frameshifting involves a novel 3 stimulatory element (see below) and is dependent on viral infection, suggestive of a regulatory aspect.