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 studies of Phil Farabaugh's group on the expression of Transposons of yeast, Ty elements, is a classic in the study of +1 frameshifting and is pertinent for other +1 S. cerevisiae frameshifting. In contrast to IS element usage of −1 frameshifting, S. cerevisiae Ty1, 2, 3 and 4 retroelements utilize +1 frameshifting near the 3 end of their gag-homologue gene to synthesize the GagPol polyprotein from which Pol and ultimately reverse transcriptase, is derived. Ty1 and Ty3 are present in up to 30 copies and 1-5 copies per cell, respectively, and their frameshifting is distinctive. Ty1 frameshifting was discovered at an early stage (206) (207) (208) . It utilizes a highly shift-prone site; 40% frameshifting was recorded with reporter constructs (209) . Yet its ratio of GagPol to Gag is only 3% (210) , much closer to that of other mobile elements. After the cap at the 5 end of the mRNA there is a pseudoknot that includes the start of the coding sequence but it serves to only modestly reduce the level of gag translation (211) . Though it does not yield accurate quantitation, the results from ribosome profiling for both Ty1 and another gene, ABP140, with the same shift site in their native chromosomal states clearly point toward the efficiency deduced from the reporter construct work ((212); A. Michel and PVB, unpublished). The discrepancy for Ty1 between 40% frameshifting and the much lower ratio of GagPol to Gag is currently ascribed to either a translational elongation effect in decoding the downstream pol gene, or reduced stability of GagPol compared to Gag (213) . The frameshifting utilized by another Ty element, Ty3 is mechanistically quite distinct (214, 215) . Its frameshifting is not a constitutive process but is regulated over a 10-fold response window depending on carbon source. The glucose-signaling pathway involved has been investigated in depth (216) .