Structural and functional conservation of the programmed −1 ribosomal frameshift signal of SARS-CoV-2

Ja, Kelly; An, Olson; Neupane, Krishna; Munshi, Sneha; Js, Emeterio; Pollack, Lois; Mt, Woodside; Dinman, Jonathan D.

doi:10.1101/2020.03.13.991083

Cited by 35 publications

(53 citation statements)

References 21 publications

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“…3b ). The ScanFold-Fold model of the FSE is largely consistent with recent models 7,19 . This model consists of two stable hairpins: the first of which contains a loop sequence which forms a pseudoknot by pairing with nucleotides upstream of the second hairpin ( Fig.…”

Section: Resultssupporting

confidence: 81%

Anin silicomap of the SARS-CoV-2 RNA Structurome

Andrews

Haniff

et al. 2020

Preprint

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SARS-CoV-2 is a positive-sense single-stranded RNA virus that has exploded throughout the global human population. This pandemic coronavirus strain has taken scientists and public health researchers by surprise and knowledge of its basic biology (e.g. structure/function relationships in its genomic, messenger and template RNAs) and modes for therapeutic intervention lag behind that of other human pathogens. In this report we used a recently-developed bioinformatics approach, ScanFold, to deduce the RNA structural landscape of the SARS-CoV-2 transcriptome. We recapitulate known elements of RNA structure and provide a model for the folding of an essential frameshift signal. Our results find that the SARS-CoV-2 is greatly enriched in unusually stable and likely evolutionarily ordered RNA structure, which provides a huge reservoir of potential drug targets for RNA-binding small molecules. Our results also predict regions that are accessible for intermolecular interactions, which can aid in the design of antisense therapeutics. All results are made available via a public database (the RNAStructuromeDB) where they may hopefully drive drug discovery efforts to inhibit SARS-CoV-2 pathogenesis. Δ G° z-score region is the 3′UTR, which was found to yield mostly positive z-scores; despite a higher than average GC content for this region (0.45 on average; Table S1), MFE values here were less stable than expected, averaging Δ G° z-scores of +0.98 (or roughly one standard deviation less stable than random). Scans were also performed in the negative sense of the genome, revealing slightly less propensity for structure. The MFE values ranged from -42.9 to -6.0 and averaged -23.25 kcal/mol; z-scores in the negative sense had a similar range of Δ G° z-scores as the positive sense (-5.76 to 2.66) but averaged lower at -1.12 (Table S1). Interestingly, Δ G° z-scores for the 3′ UTR in negative sense were more skewed to the negative (finding minimums as low as -2.32) resulting in an average z-score of 0.16 for the region.

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Section: Resultssupporting

confidence: 81%

Anin silicomap of the SARS-CoV-2 RNA Structurome

Andrews

Haniff

et al. 2020

Preprint

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“…For instance, SL6 and SL7 in the 5´ UTR are built based on computer modeling. As another example, the frame-shifting element structure presented here differs in two base pairs compared to that presented by Kelly and Dinman (Kelly and Dinman 2020).…”

Section: Discussionmentioning

confidence: 90%

RNA genome conservation and secondary structure in SARS-CoV-2 and SARS-related viruses: a first look

Rangan

Zheludev

Hagey

et al. 2020

RNA

242

401

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As the COVID-19 outbreak spreads, there is a growing need for a compilation of conserved RNA genome regions in the SARS-CoV-2 virus along with their structural propensities to guide development of antivirals and diagnostics. Here we present a first look at RNA sequence conservation and structural propensities in the SARS-CoV-2 genome. Using sequence alignments spanning a range of betacoronaviruses, we rank genomic regions by RNA sequence conservation, identifying 79 regions of length at least 15 nucleotides as exactly conserved over SARS-related complete genome sequences available near the beginning of the COVID-19 outbreak. We then confirm the conservation of the majority of these genome regions across 739 SARS-CoV-2 sequences subsequently reported from the COVID-19 outbreak, and we present a curated list of 30 'SARS-related-conserved' regions. We find that known RNA structured elements curated as Rfam families and in prior literature are enriched in these conserved genome regions, and we predict additional conserved, stable secondary structures across the viral genome. We provide 106 'SARS-CoV-2-conserved-structured' regions as potential targets for antivirals that bind to structured RNA. We further provide detailed secondary structure models for the extended 5´ UTR, frame-shifting element, and 3´ UTR. Last, we predict regions of the SARS-CoV-2 viral genome that have low propensity for RNA secondary structure and are conserved within SARS-CoV-2 strains. These 59 'SARS-CoV-2-conserved-unstructured' genomic regions may be most easily targeted in primer-based diagnostic and oligonucleotidebased therapeutic strategies.Cold Spring Harbor Laboratory Press on June 9, 2020 -Published by rnajournal.cshlp.org Downloaded from , Connelly, et al. 2016, Spurgers, et al. 2008).Conserved structured RNA regions have already been shown to play critical functional roles in the life cycles of coronaviruses. Most coronavirus 5´ UTR's harbor at least four stem loops, with many showing heightened sequence conservation across betacoronaviruses, and various stems demonstrating functional roles in viral replication (Yang and Leibowitz 2015). Furthermore, RNA secondary structure in the 5´ UTR exposes a critical sequence motif, the transcriptional regulatory sequence (TRS), that forms long-range RNA interactions necessary for facilitating the discontinuous transcription characteristic to coronaviruses (van den Born, et al. 2005). Beyond the 5´ UTR, the frame-shifting element (FSE) in the first protein-coding ORF (ORF1ab) includes a pseudoknot structure that is necessary for the production of ORF1a and ORF1b from two Cold Spring Harbor Laboratory Press on June 9, 2020 -Published by rnajournal.cshlp.org Downloaded from Results RNA sequence conservation in SARS-related betacoronaviruses and SARS-CoV-2 Cold Spring Harbor Laboratory Press on June 9, 2020 -Published by rnajournal.cshlp.org Downloaded from 1. The first multiple sequence alignment (SARSr-MSA-1) was computed by aligning sequences curated by Ceraolo and Giorgi (Ceraolo and Giorgi 2...

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“…As another example, the frame-shifting element structure presented here differs in two base pairs compared to that presented by Kelly and Dinman. 25 Additional biochemical and genetic verification, particularly through compensatory mutagenesis, will be needed to further assess these structures.…”

Section: Discussionmentioning

confidence: 99%

“…7 This domain is nearly exactly conserved between SARS-CoV and SARS-CoV-2, suggesting a similar mechanism for ribosomal pausing and slippage between the two viruses. 25 The 3´ UTR contains various domains critical for regulating viral RNA synthesis and potentially translation. The most 5´ region of the 3´ UTR includes a switch-like domain involving mutually exclusive formation of a pseudoknot and stem-loop, both of which are essential for viral replication with putative roles in establishing the kinetics of RNA synthesis.…”

Section: Secondary Structure Models For Canonical Structured Regions mentioning

confidence: 99%

RNA genome conservation and secondary structure in SARS-CoV-2 and SARS-related viruses

Rangan

Zheludev

Das

2020

Preprint

View full text Add to dashboard Cite

As the COVID-19 outbreak spreads, there is a growing need for a compilation of conserved RNA genome regions in the SARS-CoV-2 virus along with their structural propensities to guide development of antivirals and diagnostics. Using sequence alignments spanning a range of betacoronaviruses, we rank genomic regions by RNA sequence conservation, identifying 79 regions of length at least 15 nucleotides as exactly conserved over SARS-related complete genome sequences available near the beginning of the COVID-19 outbreak. We then confirm the conservation of the majority of these genome regions across 739 SARS-CoV-2 sequences reported to date from the current COVID-19 outbreak, and we present a curated list of 30 'SARS-relatedconserved' regions. We find that known RNA structured elements curated as Rfam families and in prior literature are enriched in these conserved genome regions, and we predict additional conserved, stable secondary structures across the viral genome. We provide 106 'SARS-CoV-2conserved-structured' regions as potential targets for antivirals that bind to structured RNA. We further provide detailed secondary structure models for the 5´ UTR, frame-shifting element, and 3´ UTR. Last, we predict regions of the SARS-CoV-2 viral genome have low propensity for RNA secondary structure and are conserved within SARS-CoV-2 strains. These 59 'SARS-CoV-2conserved-unstructured' genomic regions may be most easily targeted in primer-based diagnostic and oligonucleotide-based therapeutic strategies.

show abstract

Structural and functional conservation of the programmed −1 ribosomal frameshift signal of SARS-CoV-2

Cited by 35 publications

References 21 publications

Anin silicomap of the SARS-CoV-2 RNA Structurome

Anin silicomap of the SARS-CoV-2 RNA Structurome

RNA genome conservation and secondary structure in SARS-CoV-2 and SARS-related viruses: a first look

RNA genome conservation and secondary structure in SARS-CoV-2 and SARS-related viruses

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