Detection of A-to-I RNA Editing in SARS-COV-2

Picardi, Ernesto; Mansi, Luigi; Pesole, Graziano

doi:10.3390/genes13010041

Cited by 27 publications

(33 citation statements)

References 54 publications

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“…Soon after the beginning of the COVID-19 pandemic, RNA sequencing data from bronchoalveolar lavage fluid of patients with COVID-19 was used to monitor the mutational signatures shaping the viral genome before fitness selection 91 , 92 . The most common mutations detected in these sequencing data were A-to-G and T-to-C changes (possibly the outcome of ADAR1 activity on the positive-sense and negative-sense strands, respectively, during viral replication) followed by C-to-T and G-to-A changes, likely mediated by APOBEC3 proteins, the only AID/APOBEC family members known to bind and deaminate viral RNA 91 – 93 . The involvement of APOBEC3 proteins is further supported by the frequent occurrence of edited Cs within the motif 5′-U/ACU/A-3′ (refs 91 , 94 ) (although a recent preprint indicates this could also be explained by APOBEC1-mediated deamination 95 ) and in terminal loop rather than stem sequences 96 , and the upregulation of APOBEC3 proteins in samples from patients with COVID 97 – 100 .…”

Section: Aid/apobecs Drive Adaptive Evolutionmentioning

confidence: 89%

Functions and consequences of AID/APOBEC-mediated DNA and RNA deamination

et al. 2022

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The AID/APOBEC polynucleotide cytidine deaminases have historically been classified as either DNA mutators or RNA editors based on their first identified nucleic acid substrate preference. DNA mutators can generate functional diversity at antibody genes but also cause genomic instability in cancer. RNA editors can generate informational diversity in the transcriptome of innate immune cells, and of cancer cells. Members of both classes can act as antiviral restriction factors. Recent structural work has illuminated differences and similarities between AID/APOBEC enzymes that can catalyse DNA mutation, RNA editing or both, suggesting that the strict functional classification of members of this family should be reconsidered. As many of these enzymes have been employed for targeted genome (or transcriptome) editing, a more holistic understanding will help improve the design of therapeutically relevant programmable base editors.

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Section: Aid/apobecs Drive Adaptive Evolutionmentioning

confidence: 89%

Functions and consequences of AID/APOBEC-mediated DNA and RNA deamination

et al. 2022

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“…While this paper was being revised, Picardi et al ( 51 ) published a study to examine whether and to what extent A-to-I RNA editing is present in SARS-CoV-2 in infected cell model using a previously developed pipeline ( 42 ). Although both studies focus on A-to-I RNA editing of SARS-CoV-2, our study aim to develop an RNA virus-specific editing identification pipeline, examine the viral editing status from diverse types of samples infected with SARS-CoV-2, construct an atlas of A-to-I RNA editing sites, and uncover the editing landscape and hotspots in the viral genome.…”

Section: Note Added In Proofmentioning

confidence: 99%

Virus-specific editing identification approach reveals the landscape of A-to-I editing and its impacts on SARS-CoV-2 characteristics and evolution

Song

Yang

et al. 2022

Nucleic Acids Research

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Upon SARS-CoV-2 infection, viral intermediates specifically activate the IFN response through MDA5-mediated sensing and accordingly induce ADAR1 p150 expression, which might lead to viral A-to-I RNA editing. Here, we developed an RNA virus-specific editing identification pipeline, surveyed 7622 RNA-seq data from diverse types of samples infected with SARS-CoV-2, and constructed an atlas of A-to-I RNA editing sites in SARS-CoV-2. We found that A-to-I editing was dynamically regulated, varied between tissue and cell types, and was correlated with the intensity of innate immune response. On average, 91 editing events were deposited at viral dsRNA intermediates per sample. Moreover, editing hotspots were observed, including recoding sites in the spike gene that affect viral infectivity and antigenicity. Finally, we provided evidence that RNA editing accelerated SARS-CoV-2 evolution in humans during the epidemic. Our study highlights the ability of SARS-CoV-2 to hijack components of the host antiviral machinery to edit its genome and fuel its evolution, and also provides a framework and resource for studying viral RNA editing.

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“…Given the fact that SARS-CoV-2 is an RNA virus, it is natural to believe that the fast mutation and evolution of SARS-CoV-2 are mediated by the RNA deamination systems in hosts. The ssRNA-preferring APOBEC proteins drive the C-to-U(T) deamination in the viral RNAs (Yin et al 2013), while the dsRNA-preferring ADAR proteins mediate the A-to-I(G) deamination in the viral RNAs (Bass 2002;Picardi et al 2021). These deamination events, especially the C-to-U alterations, are far more prevalent than the traditional (or natural) mutation resource (the replication errors) as inferred from the enzyme accessibility to the viral RNA (Martignano et al 2022;Zong et al 2022).…”

Section: Fast Evolution Of Sars-cov-2 Might Be Driven By Rna Deaminat...mentioning

confidence: 99%

Rampant C-to-U deamination accounts for the intrinsically high mutation rate in SARS-CoV-2 spike gene

Liu

Zhou

et al. 2022

RNA

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The high mutation rate of SARS-CoV-2 largely complicates our control of the pandemic. Particularly, it is currently unclear why the spike (S) gene has extraordinarily high mutation rate among all SARS-CoV-2 genes. By analyzing the occurrence of fixed synonymous mutations between SARS-CoV-2 and RaTG13, and profiling the DAF (derived allele frequency) of polymorphic synonymous sites among millions of world-wide SARS-CoV-2 strains, we found that both fixed and polymorphic mutations show higher mutation rates in S gene than other genes. The majority of mutation is C-to-T, representing the APOBEC-mediated C-to-U deamination instead of the previously-proposed A-to-I deamination. Both in silico and in vivo evidences indicated that S gene is more likely to be single-stranded compared to other SARS-CoV-2 genes, agreeing with the APOBEC preference on ssRNA. We conclude that the single-stranded property of S gene makes itself a favorable target for C-to-U deamination, leading to its excessively high mutation rate compared to other non-S genes. In conclusion, APOBEC, rather than ADAR, is the “editor-in-chief” of SARS-CoV-2 RNAs. This work helps us understand the molecular mechanism underlying the mutation and evolution of SARS-CoV-2, and is believed to contribute to the control of the pandemic.

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Detection of A-to-I RNA Editing in SARS-COV-2

Cited by 27 publications

References 54 publications

Functions and consequences of AID/APOBEC-mediated DNA and RNA deamination

Functions and consequences of AID/APOBEC-mediated DNA and RNA deamination

Virus-specific editing identification approach reveals the landscape of A-to-I editing and its impacts on SARS-CoV-2 characteristics and evolution

Rampant C-to-U deamination accounts for the intrinsically high mutation rate in SARS-CoV-2 spike gene

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