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.

The non-segmented negative-stranded RNA viruses, measles, mumps and Sendai (and other viruses in the same subfamily Paramyxovirinae), and also Ebola (family Filoviridae), utilize what, after many alternatives, a key investigator is now calling programmed transcriptional frameshifting (PTF) (163) to yield additional product(s) that are trans-frame encoded with respect to genomic sequence. In bovine parainfluenza virus type 3 this is manifested in a ∼300 nt stretch of its P-gene being translated in all three frames. The P protein of these viruses is essential for activity of their RNA-dependent RNA polymerases. In Sendai and measles viruses, a slippage event at a specific site by polymerase transcribing the middle of the P gene results in 30% of the mRNA having a single 'extra' G (i.e. one more G in the product than the corresponding number of Cs in the template). This mRNA encodes the V protein that neutralizes host defences. For the mumps-like viruses (genus Rubulavirus) where the mRNA derived from standard transcription encodes the V rather than the P protein, 2 Gs are inserted at high frequency with the resultant mRNAs encoding the P protein. The pattern of G inserts for each virus reflects their respective ORF possibilities, and they have a mechanism to ensure that RNA with G inserts is not packaged into virions. In contrast, Ebola virus slippage occurs during transcription of its non-structural glycoprotein gene to yield transcripts without inserts and with one or two additional As in the ratio 70, 25 and 5% that encode soluble glycoprotein, transmembrane glycoprotein and small soluble glycoprotein, respectively (164) (165) (166) . A knockout of the slippage site in a recombinant Zaire ebolavirus significantly increased cytopathogenicity indicating a role for slippage products in reducing early cytotoxicity (165, 167) .