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.

Despite early work with phages MS2 and T7 (73) (74) (75) , it was the discovery by Jacks and Varmus of ribosomal frameshifting near the end of the gag gene of the alpharetrovirus, Rous sarcoma virus, that sparked widespread interest in viral frameshifting (76) . A total of 5% of ribosomes translating gag shift to the −1 pol reading frame to synthesize the GagPol precursor that upon cleavage is the source of reverse transcriptase, an endonuclease and a specific protease (Pro) (Figure 2 ). Those ribosomes that do not frameshift quickly terminate at the end of gag. The double-stranded RNA totivirus, L-A, present in killer strains of the yeast S. cerevisiae, and a variant L-A-lus in wine yeasts, use counterpart frameshifting (the effects of the killer toxin were originally noted by L. Pasteur). Its efficiency is substantially lower (77) (78) (79) (80) (81) . Red clover powdery mildew-associated totiviruses have a related frameshift cassette (82) . A −1 frameshift event is also involved in the synthesis of the HIV 1 and 2 GagPol precursor. With all these retroviruses, the viral encoded protease involved in polyprotein cleavage is encoded from the 5 part of the pol gene and so is in-frame with the reverse transcriptase encoding sequence. However, in both mouse mammary tumor virus and human T-cell lymphotropic retroviruses (83) (beta-and deltaretroviruses respectively), a second frameshift event occurs at the end of the protease encoding sequence, pro, permitting entry to the third and pol-encoding frame. This results in the synthesis of both GagPro and GagProPol precursors. The overall efficiency of GagProPol still has to be ca. 2% to 5% (for one at the low end of this range, the efficiencies of the respective frameshifting events are 23% and 8% (62,84) (Figure 3A) . The defective endogenous retroviruses, Intracisternal A-type particles (IAP) that accumulate in endoplasmic reticulae, also use two efficient separate frameshift events to synthesize their GagProPol (85, 86) . Human endogenous retrovirus (HERV), which is highly expressed in some cancers such as colorectal carcinoma (87) , utilizes efficient frameshifting (88) . Having the reverse transcriptase being part of a Pol precursor with the Gag capsid components, facilitates its packaging into virions and in an inactive form (89) . [It has been proposed that HIV Gag-Pol frameshifting is linked to selective viral encapsidation (90) , but this has been challenged (91) .