Abracadabra, One Becomes Two: The Importance of Context in Viral −1 Programmed Ribosomal Frameshifting

Penn, Wesley D.; Mukhopadhyay, Suchetana

doi:10.1128/mbio.02468-21

Cited by 4 publications

(3 citation statements)

References 86 publications

(149 reference statements)

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“…This can obscure important contributions from distal elements and lead to unexpected, reporter-derived artifacts. The importance of context in −1PRF has been discussed recently in an excellent review (152).…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

Structural and Functional Insights into Viral Programmed Ribosomal Frameshifting

Hill

Brierley

2023

Annu. Rev. Virol.

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Protein synthesis by the ribosome is the final stage of biological information transfer and represents an irreversible commitment to gene expression. Accurate translation of messenger RNA is therefore essential to all life, and spontaneous errors by the translational machinery are highly infrequent (∼1/100,000 codons). Programmed −1 ribosomal frameshifting (−1PRF) is a mechanism in which the elongating ribosome is induced at high frequency to slip backward by one nucleotide at a defined position and to continue translation in the new reading frame. This is exploited as a translational regulation strategy by hundreds of RNA viruses, which rely on −1PRF during genome translation to control the stoichiometry of viral proteins. While early investigations of −1PRF focused on virological and biochemical aspects, the application of X-ray crystallography and cryo–electron microscopy (cryo-EM), and the advent of deep sequencing and single-molecule approaches have revealed unexpected structural diversity and mechanistic complexity. Molecular players from several model systems have now been characterized in detail, both in isolation and, more recently, in the context of the elongating ribosome. Here we provide a summary of recent advances and discuss to what extent a general model for −1PRF remains a useful way of thinking. Expected final online publication date for the Annual Review of Virology, Volume 10 is September 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

Structural and Functional Insights into Viral Programmed Ribosomal Frameshifting

Hill

Brierley

2023

Annu. Rev. Virol.

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“…Moreover, it is important to consider a general limitation of the dual luciferase approach: viral RNA can have, as well, long distance interaction. For instance, the interaction between the 3 untranslated region (UTR) and the 5 UTR of different flaviviruses is fundamental for viral replication [56], or distal elements can play a role in the modulation of the PRF [57], and these functions will not be evaluated by cloning only the small RNA portion of interest. This critical aspect was further evidenced by recent research showing that a dual luciferase assay, in which a portion of 88 nucleotides or 2 kb of the −1 PRF of SARS-CoV-2, resulted in a drastically different rate of frameshift (17% vs. 42%) [32].…”

Section: Phenotypic Assays: Dual Luciferase Assaysmentioning

confidence: 99%

Small Molecules Targeting Viral RNA

Mathez,

Cagno

2023

IJMS

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The majority of antivirals available target viral proteins; however, RNA is emerging as a new and promising antiviral target due to the presence of highly structured RNA in viral genomes fundamental for their replication cycle. Here, we discuss methods for the identification of RNA-targeting compounds, starting from the determination of RNA structures either from purified RNA or in living cells, followed by in silico screening on RNA and phenotypic assays to evaluate viral inhibition. Moreover, we review the small molecules known to target the programmed ribosomal frameshifting element of SARS-CoV-2, the internal ribosomal entry site of different viruses, and RNA elements of HIV.

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“…Despite strong limitations on spontaneous ribosomal frameshifting, many RNA viruses evade this by programming ribosomes to shift into alternate reading frames, often at frequencies of three orders of magnitude greater than the background rate, through a process called Programmed Ribosomal Frameshifting (PRF) [12][13][14][15]. It is generally accepted that RNA viruses use PRF to maximize their gene expression programs without altering their genomes [16].…”

Section: Introductionmentioning

confidence: 99%

Shiftless Is a Novel Member of the Ribosome Stress Surveillance Machinery That Has Evolved to Play a Role in Innate Immunity and Cancer Surveillance

Kelly,

Dinman

2023

Viruses

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A longstanding paradox in molecular biology has centered on the question of how very long proteins are synthesized, despite numerous measurements indicating that ribosomes spontaneously shift reading frame at rates that should preclude their ability completely translate their mRNAs. Shiftless (SFL; C19orf66) was originally identified as an interferon responsive gene encoding an antiviral protein, indicating that it is part of the innate immune response. This activity is due to its ability to bind ribosomes that have been programmed by viral sequence elements to shift reading frame. Curiously, Shiftless is constitutively expressed at low levels in mammalian cells. This study examines the effects of altering Shiftless homeostasis, revealing how it may be used by higher eukaryotes to identify and remove spontaneously frameshifted ribosomes, resolving the apparent limitation on protein length. Data also indicate that Shiftless plays a novel role in the ribosome-associated quality control program. A model is proposed wherein SFL recognizes and arrests frameshifted ribosomes, and depending on SFL protein concentrations, either leads to removal of frameshifted ribosomes while leaving mRNAs intact, or to mRNA degradation. We propose that SFL be added to the growing pantheon of proteins involved in surveilling translational fidelity and controlling gene expression in higher eukaryotes.

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Abracadabra, One Becomes Two: The Importance of Context in Viral −1 Programmed Ribosomal Frameshifting

Abstract: The constrained nature of viral genomes has allowed a translational sleight of hand known as −1 Programmed Ribosomal Frameshifting (−1 PRF) to flourish. Numerous studies have sought to tease apart the mechanisms and implications of −1PRF utilizing a few techniques.

Cited by 4 publications

References 86 publications

Structural and Functional Insights into Viral Programmed Ribosomal Frameshifting

Structural and Functional Insights into Viral Programmed Ribosomal Frameshifting

Small Molecules Targeting Viral RNA

Shiftless Is a Novel Member of the Ribosome Stress Surveillance Machinery That Has Evolved to Play a Role in Innate Immunity and Cancer Surveillance

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