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.

Many different eukaryotic mRNAs exhibit sub-cellular localization with understanding of its significance being very incomplete and interest in especially the neuron-destined mRNAs being very high. When the yeast S. cerevisiae buds several mRNAs are transported to the daughter cells in an actin dependent, but translationally independent, manner by the myosin machinery. However, the conserved Nterminal 17 amino acids of ABP140 is an actin binding domain (336,337) that co-translationally causes its mRNA to associate with actin cables and be transported to the distant pole of the mother cell, rather than to the daughter cell. Unlike much mRNA transport, this trafficking is independent of mRNA structure (338) . Zero frame codons 277-279 have a Ty1-like +1 frameshift site CUU AGG C (that involves neither Thr nor Ser tRNAs) and codon 280 is a stop codon. The doubtless substantial proportion of ribosomes diverted to the +1 frame decode a 348-codon ORF that specifies a methyltransferase, a major function of which is in formation of the 3-methylcytidine modification at position 32 of the anticodons of several tRNA Thr and tRNA Ser isoacceptors, hence the TRM140 (tRNA methyltransferase) designation (336, 339) . [Of unknown significance is that zeroframe codons 208-214 specify (DG)STSTTTS and codons 251-261 specify (DD)TTGDTTSSTTS (340) with the latter being just before a +1 frame stop codon at the end of a 171 codon ORF.] The resulting fusion of structural and enzymatic functions yields an indirect linkage of actin to tRNA modification. tRNA position 32 interacts with position 38 on the other side of the anticodon loop (341) with consequences for decoding accuracy (342) . The significance of the frameshifting and presumably of location-specific methyltransferase activity is unknown but likely related to its function in the yeast's natural environment and not in lab culture. [Why deletion strains are sensitive to neomycin is obscure (343) .] Nevertheless, given the time of divergence of the ancestors of the yeast species that have the characteristics of ABP140 frameshifting, the frameshifting has to have been occurring for 150 million years and be of selective advantage (242) . [However, S. castellii has lost the frameshift site.] ORF1 is much less conserved than ORF2 which is also conserved in other organisms that do not have fused expression with an upstream ORF.