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 E. coli dnaX shift site sequence, A AAA AAG, the sole tRNA Lys has the potential to pair with AAG or the −1 frame AAA, with pairing to the latter being stronger. There is no amino acid level distinction between two tR-NAs pairing, dissociating, realigning and both re-pairing to mRNA in the −1 frame from the entering aminoacyl tRNA pairing directly in the −1 frame. However, with U UUU UUA, the HIV shift site, cognate tRNA Leu dissociating from UUA and re-pairing to mRNA at the overlapping −1 frame UUU would result in a different amino acid compared to acceptance of incoming aminoacyl tRNA Phe into the A-site following a −1 shift involving the tRNA that had paired to zero frame UUU. Indeed the protein product from −1 frameshifting on the HIV shift site is heterogeneous with the U UUA encoding 20-30% Phe and 70-80% Leu (94, 404) and analyzed in depth (97) . [Only a trace of a product corresponding to the minor product is seen with human T-cell lymphotropic virus type 1 (HTLV-1, also known as human T-cell leukemia virus) pro-pol frameshifting (83) , and an unspecified level of counterpart was detected with alphavirus frameshifting (137) .] Further HIV frameshifting product heterogeneity comes from a proportion of the frameshifting being −2 rather than −1. Though this has only been detected so far in reticulocytes lysates and transfected cells (98) , it is likely also in infected cells.