No species-level losses of s2m suggests critical role in replication of SARS-related coronaviruses

Gilbert, Clément; Tengs, Torstein

doi:10.1038/s41598-021-95496-4

Cited by 19 publications

(23 citation statements)

References 30 publications

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“…To demonstrate the functional significance of the s2m in a different astrovirus, we introduced a partial deletion of the s2m in HAstV1 ( Table S1 ) using a published reverse genetics system 15 . As with the VA1 s2m, the HAstV1 s2m contains a stop codon for ORF2, so we introduced a deletion of 19 nucleotides after the stop codon (HAstV1-s2m Δ25–43 ). In contrast to our results with VA1, recombinant HAstV1 virus containing the deletion could be rescued and had no unexpected mutations identified by Sanger sequencing ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Our results demonstrate the SARS-CoV-2 s2m is not critical for the viral lifecycle. There are multiple reports of mutations and deletions of the s2m in SARS-CoV-2 clinical isolates [23][24][25][26] , and the s2m region has, surprisingly, a higher mutational rate compared to other regions of the SARS-CoV-2 genome 23 . These observations, combined with our functional data raise the possibility that SARS-CoV-2 may have evolved an alternate mechanism to substitute for the function of the s2m.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the reference SARS-CoV-2 genome and all subsequent variants of concern encode a unique genetic variant with a uracil at position 32 in the s2m that is distinct from other s2m sequences and is predicted to perturb the secondary structure [19][20][21][22][23] . Additional genetic variants or deletions of the s2m have been periodically detected from clinical isolates [23][24][25][26] .…”

Section: Introductionmentioning

confidence: 99%

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The highly conserved stem-loop II motif is important for the lifecycle of astroviruses but dispensable for SARS-CoV-2

Janowski

Jiang

Fujii

et al. 2022

Preprint

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The stem-loop II motif (s2m) is an RNA element present in viruses from divergent viral families, including astroviruses and coronaviruses, but its functional significance is unknown. We created deletions or substitutions of the s2m in astrovirus VA1 (VA1), classic human astrovirus 1 (HAstV1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For VA1, recombinant virus could not be rescued upon partial deletion of the s2m or substitutions of G-C base pairs. Compensatory substitutions that restored the G-C base-pair enabled recovery of VA1. For HAstV1, a partial deletion of the s2m resulted in decreased viral titers compared to wild-type virus, and reduced activity in a replicon system. In contrast, deletion or mutation of the SARS-CoV-2 s2m had no effect on the ability to rescue the virus, growth in vitro, or growth in Syrian hamsters. Our study demonstrates the importance of the s2m is virus-dependent.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The highly conserved stem-loop II motif is important for the lifecycle of astroviruses but dispensable for SARS-CoV-2

Janowski

Jiang

Fujii

et al. 2022

Preprint

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“…The central dogma dictates that the virus proliferation includes (at least for RNA viruses like SARS-CoV-2) the replication and translation processes. While the elements required for replication is evolutionarily conserved across coronaviruses, 2 the mechanism of virus translation is quite mysterious. This prompts us to consider how the virus translate its own RNAs in the host cells.…”

Section: Introductionmentioning

confidence: 99%

Compelling Evidence Suggesting the Codon Usage of SARS-CoV-2 Adapts to Human After the Split From RaTG13

Zhang

Jin

Wang

et al. 2021

Evol Bioinform Online

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SARS-CoV-2 needs to efficiently make use of the resources from hosts in order to survive and propagate. Among the multiple layers of regulatory network, mRNA translation is the rate-limiting step in gene expression. Synonymous codon usage usually conforms with tRNA concentration to allow fast decoding during translation. It is acknowledged that SARS-CoV-2 has adapted to the codon usage of human lungs so that the virus could rapidly proliferate in the lung environment. While this notion seems to nicely explain the adaptation of SARS-CoV-2 to lungs, it is unable to tell why other viruses do not have this advantage. In this study, we retrieve the GTEx RNA-seq data for 30 tissues (belonging to over 17 000 individuals). We calculate the RSCU (relative synonymous codon usage) weighted by gene expression in each human sample, and investigate the correlation of RSCU between the human tissues and SARS-CoV-2 or RaTG13 (the closest coronavirus to SARS-CoV-2). Lung has the highest correlation of RSCU to SARS-CoV-2 among all tissues, suggesting that the lung environment is generally suitable for SARS-CoV-2. Interestingly, for most tissues, SARS-CoV-2 has higher correlations with the human samples compared with the RaTG13-human correlation. This difference is most significant for lungs. In conclusion, the codon usage of SARS-CoV-2 has adapted to human lungs to allow fast decoding and translation. This adaptation probably took place after SARS-CoV-2 split from RaTG13 because RaTG13 is less perfectly correlated with human. This finding depicts the trajectory of adaptive evolution from ancestral sequence to SARS-CoV-2, and also well explains why SARS-CoV-2 rather than other viruses could perfectly adapt to human lung environment.

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“…Recently, a novel L -DNA aptamer was successfully identified as targeting the stem-loop II-like motif (s2m), which is a highly conserved structure at the 3′-UTR region of the RNA genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [ 100 ]. The 41-nucleotide s2m element is discovered in coronavirus, astrovirus, and equine rhinovirus genomes, and it plays a critical role in viral replication and packaging [ 101 ]. Therefore, s2m structure is an effective and popular target in anti-viral drug design.…”

Section: L -Nuclei Acid Aptamers To Target Disease-related Elementsmentioning

confidence: 99%

Advances in Therapeutic L-Nucleosides and L-Nucleic Acids with Unusual Handedness

Dantsu

Zhang

2021

Genes

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Nucleic-acid-based small molecule and oligonucleotide therapies are attractive topics due to their potential for effective target of disease-related modules and specific control of disease gene expression. As the non-naturally occurring biomolecules, modified DNA/RNA nucleoside and oligonucleotide analogues composed of L-(deoxy)riboses, have been designed and applied as innovative therapeutics with superior plasma stability, weakened cytotoxicity, and inexistent immunogenicity. Although all the chiral centers in the backbone are mirror converted from the natural D-nucleic acids, L-nucleic acids are equipped with the same nucleobases (A, G, C and U or T), which are critical to maintain the programmability and form adaptable tertiary structures for target binding. The types of L-nucleic acid drugs are increasingly varied, from chemically modified nucleoside analogues that interact with pathogenic polymerases to nanoparticles containing hundreds of repeating L-nucleotides that circulate durably in vivo. This article mainly reviews three different aspects of L-nucleic acid therapies, including pharmacological L-nucleosides, Spiegelmers as specific target-binding aptamers, and L-nanostructures as effective drug-delivery devices.

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No species-level losses of s2m suggests critical role in replication of SARS-related coronaviruses

Cited by 19 publications

References 30 publications

The highly conserved stem-loop II motif is important for the lifecycle of astroviruses but dispensable for SARS-CoV-2

The highly conserved stem-loop II motif is important for the lifecycle of astroviruses but dispensable for SARS-CoV-2

Compelling Evidence Suggesting the Codon Usage of SARS-CoV-2 Adapts to Human After the Split From RaTG13

Advances in Therapeutic L-Nucleosides and L-Nucleic Acids with Unusual Handedness

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