Regulation of Programmed Ribosomal Frameshifting by Co-Translational Refolding RNA Hairpins

Cho, Che-Pei; Lin, Szu-Chieh; Chou, Ming-Yuan; Hsu, Hsiu‐Ting; Chang, Kai-Hsiang

doi:10.1371/journal.pone.0062283

Cited by 41 publications

(56 citation statements)

References 31 publications

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“…Deletion of SLA enhanced frameshifting to 72% of WT in the RSE background ( Figure 9C; RSE versus RSE+ SLA*), strongly suggesting that a hairpin upstream of the slippery site suppresses downstream frameshifting when an RSE is not present (or not formed). A previous study also revealed a suppressive role for a hairpin located 4-nt upstream of the slippery site in SARS-CoV, and this hairpin was able to suppress frameshifting stimulated by pseudoknots from a number of different viruses (31,64). The level of attenuation reported was sensitive to the stability of the stem as well as the distance from the slippery site (64).…”

Section: Possible Role For the Phylogenetically Conserved Sla Hairpinmentioning

confidence: 81%

“…A previous study also revealed a suppressive role for a hairpin located 4-nt upstream of the slippery site in SARS-CoV, and this hairpin was able to suppress frameshifting stimulated by pseudoknots from a number of different viruses (31,64). The level of attenuation reported was sensitive to the stability of the stem as well as the distance from the slippery site (64). In PEMV, the basal portion of the SLA stem would be melted when a ribosome is positioned at the slippery sequence, but the remainder of the hairpin may provide mechanical resistance for 5 movement of the ribosome, thus suppressing frameshifting.…”

Section: Possible Role For the Phylogenetically Conserved Sla Hairpinmentioning

confidence: 86%

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Multiple Cis-acting elements modulate programmed -1 ribosomal frameshifting in Pea enation mosaic virus

Gao

Simon

2015

Nucleic Acids Research

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Programmed -1 ribosomal frameshifting (-1 PRF) is used by many positive-strand RNA viruses for translation of required products. Despite extensive studies, it remains unresolved how cis-elements just downstream of the recoding site promote a precise level of frameshifting. The Umbravirus Pea enation mosaic virus RNA2 expresses its RNA polymerase by -1 PRF of the 5′-proximal ORF (p33). Three hairpins located in the vicinity of the recoding site are phylogenetically conserved among Umbraviruses. The central Recoding Stimulatory Element (RSE), located downstream of the p33 termination codon, is a large hairpin with two asymmetric internal loops. Mutational analyses revealed that sequences throughout the RSE and the RSE lower stem (LS) structure are important for frameshifting. SHAPE probing of mutants indicated the presence of higher order structure, and sequences in the LS may also adapt an alternative conformation. Long-distance pairing between the RSE and a 3′ terminal hairpin was less critical when the LS structure was stabilized. A basal level of frameshifting occurring in the absence of the RSE increases to 72% of wild-type when a hairpin upstream of the slippery site is also deleted. These results suggest that suppression of frameshifting may be needed in the absence of an active RSE conformation.

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Section: Possible Role For the Phylogenetically Conserved Sla Hairpinmentioning

confidence: 81%

Section: Possible Role For the Phylogenetically Conserved Sla Hairpinmentioning

confidence: 86%

Multiple Cis-acting elements modulate programmed -1 ribosomal frameshifting in Pea enation mosaic virus

Gao

Simon

2015

Nucleic Acids Research

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“…(C) Proposed basal SLA structure for SARS-CoV. The upstream SLA hairpin serves as a repressor of PRF (33)(34)(35). Sequences shown in blue are capable of pairing.…”

Section: Conserved Features Of Tombusvirid Rsesmentioning

confidence: 99%

“…Since internal H-type pseudoknots have not been reported in RSEs from any of these plant viruses, it has been proposed that these long-distance RNA bridges form an atypical pseudoknot that functionally replaces the internal pseudoknot that is common in animal virus RSEs (2,28,32). In addition, hairpins or artificial duplexes just upstream of the recoding site repress frameshifting in coronaviruses and PEMV2 (21,(33)(34)(35). Strikingly, in the absence of the upstream hairpin, the PEMV2 RSE is no longer required to stimulate frameshifting from the slippery site, suggesting that upstream hairpins may play significant roles in suppressing Ϫ1PRF.…”

mentioning

confidence: 99%

An RNA Element That Facilitates Programmed Ribosomal Readthrough in Turnip Crinkle Virus Adopts Multiple Conformations

Kuhlmann

Chattopadhyay

Stupina

et al. 2016

J Virol

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Ribosome recoding is used by RNA viruses for translational readthrough or frameshifting past termination codons for the synthesis of extension products. Recoding sites, along with downstream recoding stimulatory elements (RSEs), have long been studied in reporter constructs, because these fragments alone mediate customary levels of recoding and are thus assumed to contain complete instructions for establishment of the proper ratio of termination to recoding. RSEs from the Tombusviridae and Luteoviridae are thought to be exceptions, since they contain a long-distance RNA-RNA connection with the 3= end. This interaction has been suggested to substitute for pseudoknots, thought to be missing in tombusvirid RSEs. We provide evidence that the phylogenetically conserved RSE of the carmovirus Turnip crinkle virus (TCV) adopts an alternative, smaller structure that extends an upstream conserved hairpin and that this alternative structure is the predominant form of the RSE within nascent viral RNA in plant cells and when RNA is synthesized in vitro. The TCV RSE also contains an internal pseudoknot along with the long-distance interaction, and the pseudoknot is not compatible with the phylogenetically conserved structure. Conserved residues just past the recoding site are important for recoding, and these residues are also conserved in the RSEs of gammaretroviruses. Our data demonstrate the dynamic nature of the TCV RSE and suggest that studies using reporter constructs may not be effectively recapitulating RSE-mediated recoding within viral genomes. IMPORTANCERibosome recoding is used by RNA viruses to enable ribosomes to extend translation past termination codons for the synthesis of longer products. Recoding sites and a downstream recoding stimulatory element (RSE) mediate expected levels of recoding when excised and placed in reporter constructs and thus are assumed to contain complete instructions for the establishment of the proper ratio of termination to recoding. We provide evidence that most of the TCV RSE adopts an alternative structure that extends an upstream conserved hairpin and that this alternative structure, and not the phylogenetically conserved structure, is the predominant form of the RSE in RNA synthesized in vitro and in plant cells. The TCV RSE also contains an internal pseudoknot that is not compatible with the phylogenetically conserved structure and an RNA bridge to the 3= end. These data suggest that the TCV RSE is structurally dynamic and that multiple conformations are likely required to regulate ribosomal readthrough. P ositive-sense RNA viruses employ a variety of gene expression strategies for the diversification of their proteomes (1, 2). Two noncanonical mechanisms, Ϫ1 programmed ribosomal frameshifting (Ϫ1PRF) and programmed ribosomal readthrough (PRT), circumvent stop codons for the expression of carboxyterminal extension products, effectively economizing on the limited genome size of most RNA viruses (3, 4). In Ϫ1PRF, the elongating ribosome shifts back 1 residue at a 7-residue...

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“…Conversely, the upstream hairpin in barley yellow dwarf virus (genus Luteovirus, family Luteoviridae, but related to tombusvirids) (43) was found to enhance frameshifting (18). In a third example, severe acute respiratory syndrome coronavirus, the upstream hairpin downregulated frameshifting activity (10). Thus, the effects of such RNA structures on frameshifting can vary significantly.…”

Section: Structural Features Of the Upper Portion Of The Rtsl Moderatmentioning

confidence: 99%

Atypical RNA Elements Modulate Translational Readthrough in Tobacco Necrosis Virus D

Newburn

White

2017

J Virol

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Tobacco necrosis virus, strain D (TNV-D), is a positive-strand RNA virus in the genus and family The production of its RNA-dependent RNA polymerase, p82, is achieved by translational readthrough. This process is stimulated by an RNA structure that is positioned immediately downstream of the recoding site, termed the readthrough stem-loop (RTSL), and a sequence in the 3' untranslated region of the TNV-D genome, called the distal readthrough element (DRTE). Notably, a base pairing interaction between the RTSL and the DRTE, spanning ∼3,000 nucleotides, is required for enhancement of readthrough. Here, some of the structural features of the RTSL, as well as RNA sequences and structures that flank either the RTSL or DRTE, were investigated for their involvement in translational readthrough and virus infectivity. The results revealed that (i) the RTSL-DRTE interaction cannot be functionally replaced by stabilizing the RTSL structure, (ii) a novel tertiary RNA structure positioned just 3' to the RTSL is required for optimal translational readthrough and virus infectivity, and (iii) these same activities also rely on an RNA stem-loop located immediately upstream of the DRTE. Functional counterparts for the RTSL-proximal structure may also be present in other tombusvirids. The identification of additional distinct RNA structures that modulate readthrough suggests that regulation of this process by genomic features may be more complex than previously appreciated. Possible roles for these novel RNA elements are discussed. The analysis of factors that affect recoding events in viruses is leading to an ever more complex picture of this important process. In this study, two new atypical RNA elements were shown to contribute to efficient translational readthrough of the TNV-D polymerase and to mediate robust viral genome accumulation in infections. One of the structures, located close to the recoding site, could have functional equivalents in related genera, while the other structure, positioned 3' proximally in the viral genome, is likely limited to betanecroviruses. Irrespective of their prevalence, the identification of these novel RNA elements adds to the current repertoire of viral genome-based modulators of translational readthrough and provides a notable example of the complexity of regulation of this process.

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Regulation of Programmed Ribosomal Frameshifting by Co-Translational Refolding RNA Hairpins

Cited by 41 publications

References 31 publications

Multiple Cis-acting elements modulate programmed -1 ribosomal frameshifting in Pea enation mosaic virus

Multiple Cis-acting elements modulate programmed -1 ribosomal frameshifting in Pea enation mosaic virus

An RNA Element That Facilitates Programmed Ribosomal Readthrough in Turnip Crinkle Virus Adopts Multiple Conformations

Atypical RNA Elements Modulate Translational Readthrough in Tobacco Necrosis Virus D

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