Ribosomal frameshifting viruses

Among these signals, an mRNA pseudoknot may direct ribosomes to pause at the slippery site. Edr and PEG10 are members of a large family of functional neogenes called Mart for mammalian retrotransposon derived that are widely distributed among mammals, and appear to be related to the gag gene of repeat retrotransposons. The functions of these frameshift are unknown.

The first such search found that these were represented in coding regions of eukaryotic genomes as much as sixfold more frequently than would be expected if distribution were random. The reliance of the fourth on known stimulatory elements would seem to preclude its ability to identify new ones, although it has potentially uncovered a new posttranscriptional means for regulating gene expression. For instance, one recent study involved a two-step approach combining a search for overlapping ORFs with Hidden Markov Models.

It identified candidate PRF-related genes in the S. Researchers are currently working to identify the mRNA decay pathways involved and to determine how each of them destabilizes mRNA.

Model of mRNA suicide by frameshifting. When PRF was discovered, investigators surmised that it was an evolutionarily recent development specific to a few RNA viruses. However, the emerging picture of PRF as a widely distributed posttranscriptional regulatory mechanism suggests the opposite is true and that PRF might be a remnant of the extremely old, prebiotic RNA world.

The ability of a molecule of RNA to encode more than one outcome would add to the information content of cells bearing it without altering its sequence, providing that molecule with a greater range of options. Looking forward, PRF is more than a mere curiosity specific to a few exceptional viruses.

Rather, the field entails a far wider variety of organisms and thus is expanding in many exciting directions. The discovery and characterization of new mechanisms of PRF will further expand our understanding of the interplay between ribosomes and cis -acting signals encoded in mRNAs. With that door opened, other important possibilities are manifold: maybe PRF regulates development and, the flip side of this coin, diseases such as birth defects and cancer that arise when development is dysregulated.

I would like to thank the students and postdocs who have done all of the heavy lifting in my lab over the past decade or so. National Center for Biotechnology Information , U. Microbe Wash DC. Author manuscript; available in PMC May Organisms from all three kingdoms use frameshifting to regulate gene expression, perhaps signaling a paradigm shift.

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This article has been cited by other articles in PMC. Associated Data Supplementary Materials science. Open in a separate window. Critical features of the ribosome-bound pseudoknot. The pseudoknot causes ribosomal pausing prior to -1 frameshifting The observation that the pseudoknot acts as an obstacle to slow down translation as the ribosome approaches the slippery site is mechanistically reasonable. Pseudoknot-mediated pause occurs prior to the -1 frameshifting event.

Nascent chain forms specific interactions with the ribosomal exit tunnel Strikingly, in the reconstruction of the paused translating ribosome, the nascent chain that corresponds to the viral polyprotein was visible along the entire length of the ribosomal exit tunnel Fig.

The nascent viral polypeptide co-translationally folds and specifically interacts with the ribosomal tunnel. Inhibition of viral replication by a compound that targets the SARS-CoV-2 pseudoknot The sensitivity of the coronavirus to the finely controlled frameshifting levels 13 may present an opportunity to develop compounds that interfere with the frameshifting process and thus inhibit replication of the virus.

Conclusions Our results provide a mechanistic description of frameshifting that occurs during translation of the SARS-CoV-2 genome and reveal the features that may be exploited by the virus to finely control the stoichiometry of viral proteins at different stages of infection Fig.

Structure based model for -1 programmed frameshifting in coronaviruses and its regulation. Acknowledgments We thank A. Supplementary Materials science. References and Notes 1. Parker J. Ogle J. Trends Biochem. Atkins J. Nucleic Acids Res.

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