Published online 19 July 2016 Nucleic Acids Research, 2016, Vol. 44, No. 15 7007–7078 doi: 10.1093/nar/gkw530
SURVEY AND SUMMARY Ribosomal frameshifting and transcriptional slippage: From genetic steganography and cryptography to adventitious use John F. Atkins1,2,3,*, Gary Loughran1, Pramod R. Bhatt1, Andrew E. Firth4 and Pavel V. Baranov1
1School of Biochemistry and Cell Biology, University College Cork, Cork, Ireland, 2School of Microbiology, University College Cork, Cork, Ireland, 3Department of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA and 4Division of Virology, Department of Pathology, University of Cambridge, Hills Road, Cambridge CB2 0QQ, UK
Received March 21, 2016; Revised May 20, 2016; Accepted May 26, 2016
ABSTRACT INTRODUCTION Genetic decoding is not ‘frozen’ as was earlier AUG. Doubtless applicability of the word ‘steganography’ thought, but dynamic. One facet of this is frameshift- to certain forms of genetic recoding and frameshifting in ing that often results in synthesis of a C-terminal re- particular, was not envisaged when it was first used in 1499 gion encoded by a new frame. Ribosomal frameshift- to mean an intended secret message that does not attract ing is utilized for the synthesis of additional prod- attention in contrast to cryptography where just the con- tents of the hidden message is protected and not its ex- ucts, for regulatory purposes and for translational istence. Nevertheless, its use in connection with produc- ‘correction’ of problem or ‘savior’ indels. Utilization tively utilized frameshifting by Patrick Moore (1) highlights for synthesis of additional products occurs promi- the extra N-terminally coincident product(s) whose syn- nently in the decoding of mobile chromosomal el- thesis involves a switch from the frame set at initiation to ement and viral genomes. One class of regulatory one of the two alternative reading frames (registers) inher- frameshifting of stable chromosomal genes governs ent with standard non-overlapping triplet decoding (Fig- cellular polyamine levels from yeasts to humans. ure 1). The frameshift-derived product is generally quite In many cases of productively utilized frameshift- different in both length and sequence from the product ing, the proportion of ribosomes that frameshift at of standard decoding. It is not only ribosomal frameshift- a shift-prone site is enhanced by specific nascent ing that can yield a trans-frame encoded protein, but also peptide or mRNA context features. Such mRNA sig- where the RNA polymerase ‘slips’ to yield mRNA lacking or containing one or more extra bases (that are not 3 nt or nals, which can be 5 or 3 of the shift site or both, can multiples thereof). Such ‘transcriptional frameshifting’ also act by pairing with ribosomal RNA or as stem loops yields products that are trans-frame specified with respect to or pseudoknots even with one component being 4 sequence present in the encoding DNA (or RNA in the case kb 3 from the shift site. Transcriptional realignment of some viruses). at slippage-prone sequences also generates produc- To commemorate this year the 50th anniversary of the tively utilized products encoded trans-frame with re- full-deciphering of the genetic code and the 100th anniver- spect to the genomic sequence. This too can be en- sary of Crick’s birth, we provide an overview of knowledge hanced by nucleic acid structure. Together with dy- gained since then on the aspects of the dynamic nature of namic codon redefinition, frameshifting is one of the both mRNA generation and code readout gained by study- forms of recoding that enriches gene expression. ing frameshifting, especially ribosomal frameshifting. For space reasons, other features of the ‘extra layer’ in code readout, including dynamic codon redefinition and other processes that yield a trans-frame encoded product with re- spect to the DNA will generally be omitted (even though
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