The Roles of APOBEC-mediated RNA Editing in SARS-CoV-2 Mutations, Replication, and Fitness

During COVID-19 pandemic, mutations of SARS-CoV-2 produce new strains that can be more infectious or evade vaccines. Viral RNA mutations can arise from misincorporation by RNA-polymerases and modification by host factors. Analysis of SARS-CoV-2 sequence from patients showed a strong bias toward C-to...

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Bibliographic Details
Published in:bioRxiv 2022-04
Main Authors: Kim, Kyumin, Calabrese, Peter, Wang, Shanshan, Chao, Qin, Rao, Youliang, Feng, Pinghui, Chen, Xiaojiang
Format: Article
Language:English
Subjects:
Antiviral agents
COVID-19
Cytosine
Editing
Mutation
Nucleotide sequence
Pandemics
Replication
Reproductive fitness
Ribonucleic acid
RNA
RNA editing
RNA modification
Severe acute respiratory syndrome coronavirus 2
Vaccines
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Summary:During COVID-19 pandemic, mutations of SARS-CoV-2 produce new strains that can be more infectious or evade vaccines. Viral RNA mutations can arise from misincorporation by RNA-polymerases and modification by host factors. Analysis of SARS-CoV-2 sequence from patients showed a strong bias toward C-to-U mutation, suggesting a potential mutational role by host APOBEC cytosine deaminases that possess broad anti-viral activity. We report the first experimental evidence demonstrating that APOBEC3A, APOBEC1, and APOBEC3G can edit on specific sites of SARS-CoV-2 RNA to produce C-to-U mutations. However, SARS-CoV-2 replication and viral progeny production in Caco-2 cells are not inhibited by the expression of these APOBECs. Instead, the expression of wild-type APOBEC3 greatly promotes viral replication/propagation, suggesting that SARS-CoV-2 utilizes the APOBEC-mediated mutations for fitness and evolution. Unlike the random mutations, this study suggests the predictability of all possible viral genome mutations by these APOBECs based on the UC/AC motifs and the viral genomic RNA structure. Competing Interest Statement The authors have declared no competing interest. Footnotes * Added viral replication and infection data on A3A knockout and A3A inactive mutant expressing cell lines. Added Supplementary data. And expand on the discussion section, with two extra supplementary figures.
DOI:10.1101/2021.12.18.473309