The role of programmed-1 ribosomal frameshifting in coronavirus propagation

Division of Emerging and Transfusion Transmitted Diseases, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
Frontiers in Bioscience (Impact Factor: 3.52). 02/2008; 13(13):4873-81. DOI: 10.2741/3046
Source: PubMed


Coronaviruses have the potential to cause significant economic, agricultural and health problems. The severe acute respiratory syndrome (SARS) associated coronavirus outbreak in late 2002, early 2003 called attention to the potential damage that coronaviruses could cause in the human population. The ensuing research has enlightened many to the molecular biology of coronaviruses. A programmed -1 ribosomal frameshift is required by coronaviruses for the production of the RNA dependent RNA polymerase which in turn is essential for viral replication. The frameshifting signal encoded in the viral genome has additional features that are not essential for frameshifting. Elucidation of the differences between coronavirus frameshift signals and signals from other viruses may help our understanding of these features. Here we summarize current knowledge and add additional insight regarding the function of the programmed -1 ribosomal frameshift signal in the coronavirus lifecycle.

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Available from: Jonathan D Dinman
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    • "The protein elongation by the ribosome is a precise process, with an error frequency estimated to be less than 3 Â 10 À5 per codon [1] [2]. However, programmed ribosomal frameshifting, i.e., translating ribosomes slipping by one base in either the 5 0 (À1) or the 3 0 (+1) direction, is the most widely used translational regulation mechanism employed by many viruses to express defined ratios of structural and enzymatic proteins [3] [4] [5] [6] [7] [8] [9] [10] [11]. It was shown that À1 frameshifting can occur at the slippery sequence on the presence of a downstream mRNA pseudoknot [6,11–15]. "
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    ABSTRACT: It has been well characterized that the amino acid starvation can induce +1 frameshifting. However, how the +1 frameshifting occurs has not been fully understood. Here, taking Escherichia coli RF2 programmed frameshifting as an example we present systematical analysis of the +1 frameshifting that could occur during every state-transition step in elongation phase of protein synthesis, showing that the +1 frameshifting can occur only during the period after deacylated tRNA dissociation from the posttranslocation state and before the recognition of the next “hungry” codon. The +1 frameshifting efficiency is theoretically studied, with the simple analytical solutions showing that the high efficiency is almost solely due to the occurrence of ribosome pausing which in turn results from the insufficient RF2. The analytical solutions also provide a consistent explanation of a lot of independent experimental data.
    Preview · Article · Mar 2014 · Mathematical biosciences
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    • "The replicase gene, which spans the 5′ two-thirds of the genome, is translated by host ribosomes into two large polyproteins, pp1a and pp1ab via a frameshift event (8–10). The polyproteins are autoproteolytically processed into a maximum of 16 nonstructural proteins (8,11–16), which are assembled into replication–transcription complexes, including the main enzyme RNA-dependent RNA polymerase (nsp12) (17,18). This complex is required for generating new full-length virus RNA in replication as well as subgenome-length RNAs to be used for translation of virus structural and accessory proteins. "
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    ABSTRACT: Coronaviruses RNA synthesis occurs in the cytoplasm and is regulated by host cell proteins. In a screen based on a yeast three-hybrid system using the 5′-untranslated region (5′-UTR) of SARS coronavirus (SARS-CoV) RNA as bait against a human cDNA library derived from HeLa cells, we found a positive candidate cellular protein, zinc finger CCHC-type and RNA-binding motif 1 (MADP1), to be able to interact with this region of the SARS-CoV genome. This interaction was subsequently confirmed in coronavirus infectious bronchitis virus (IBV). The specificity of the interaction between MADP1 and the 5′-UTR of IBV was investigated and confirmed by using an RNA pull-down assay. The RNA-binding domain was mapped to the N-terminal region of MADP1 and the protein binding sequence to stem–loop I of IBV 5′-UTR. MADP1 was found to be translocated to the cytoplasm and partially co-localized with the viral replicase/transcriptase complexes (RTCs) in IBV-infected cells, deviating from its usual nuclear localization in a normal cell using indirect immunofluorescence. Using small interfering RNA (siRNA) against MADP1, defective viral RNA synthesis was observed in the knockdown cells, therefore indicating the importance of the protein in coronaviral RNA synthesis.
    Full-text · Article · Feb 2012 · Nucleic Acids Research
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    • "In −1 PRF, the ribosome slips 1 nt towards the 5′-end of the mRNA during translation. Several viruses, including human immunodeficiency virus type 1 (HIV-1) and the coronavirus responsible for severe acute respiratory syndrome (SARS-CoV), employ −1 PRF to synthesize precursors of enzymes for their replication (1,2), and the ratio of the zero frame to −1 frame encoded products is important to the vitality of viruses (3–5). As such, altering −1 PRF efficiency may damage viral replication [reviewed in (6)]. "
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    ABSTRACT: Several important viruses including the human immunodeficiency virus type 1 (HIV-1) and the SARS-associated Coronavirus (SARS-CoV) employ programmed −1 ribosomal frameshifting (PRF) for their protein expression. Here, a kinetic framework is developed to describe −1 PRF. The model reveals three kinetic pathways to −1 PRF that yield two possible frameshift products: those incorporating zero frame encoded A-site tRNAs in the recoding site, and products incorporating −1 frame encoded A-site tRNAs. Using known kinetic rate constants, the individual contributions of different steps of the translation elongation cycle to −1 PRF and the ratio between two types of frameshift products were evaluated. A dual fluorescence reporter was employed in Escherichia coli to empirically test the model. Additionally, the study applied a novel mass spectrometry approach to quantify the ratios of the two frameshift products. A more detailed understanding of the mechanisms underlying −1 PRF may provide insight into developing antiviral therapeutics.
    Full-text · Article · Jan 2011 · Nucleic Acids Research
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