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.

A computational analysis of sequences from 12 Drosophila species using reading frame conservation and codon substitution frequencies showed that in the coding region of the D. melanogaster APC gene, purifying selection switched from the zero frame to the −1 frame and subsequently back to the zero frame. It was listed as a candidate for utilized frameshifting in its expression (344) . APC functions in the canonical Wnt/Wingless (Wg) signaling pathway in Drosophila and mammals (Drosophila APC is implicated in intestinal stem cell proliferation, and in mammals APC mutants are a direct cause of colon cancer). −1 frameshifting was experimentally found to occur 143 nts upstream of the computationally predicted switch of coding frame signatures (46) . Zero frame conservation only of the segment 5 of the frameshift site, and of the segment 3 of the frameshift product termination codon, implies that the part of the product of standard decoding encoded by the intervening zero-frame sequence merely serves as a linker. Significance of the frameshifting is indicated by conservation of the new frame product. Suggestive of an ancient origin of the frameshifting, it also occurs in nematodes, but interestingly, in that case the C-terminal region of the transframe product encoded by the −1 frame is much shorter (13 AA versus 125 AA) (46) . Immunoprecipitation of human APC reveals a variety of shorter than full-length products but whether any of these are frameshift derived is unknown -and not easy to analyze given the low expression level. However, a single T to A transversion that results in a run of 8 As is relatively prevalent in a specific population group where it is directly associated with colon cancer (345) . Both replicational and transcriptional slippage are likely responsible for the causative protein products whose synthesis is prematurely terminated by stop codons that are not in the WT zero frame (345, 346) .