Biochemical simulation of mutation synthesis and repair during SARS-CoV-2 RNA polymerization

We biochemically simulated the mutation synthesis process of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) complex (nsp7/nsp8/nsp12) involving two sequential mechanistic steps that occur during genomic replication: misinsertion (incorporation of incorrect nucleotides) and mismatch extension. Then,...

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Published in:Virology (New York, N.Y.) Vol. 600; p. 110255
Main Authors: Oo, Adrian, Chen, Zhenhang, Cao, Dongdong, Cho, Young-Jae, Liang, Bo, Schinazi, Raymond F, Kim, Baek
Format: Journal Article
Language:English
Published: United States 01.12.2024
Subjects:
Coronavirus RNA-Dependent RNA Polymerase - genetics
Coronavirus RNA-Dependent RNA Polymerase - metabolism
COVID-19 - virology
Genome, Viral
Humans
Mutation
Polymerization
RNA, Viral - biosynthesis
RNA, Viral - genetics
RNA, Viral - metabolism
RNA-Dependent RNA Polymerase - genetics
RNA-Dependent RNA Polymerase - metabolism
SARS-CoV-2 - genetics
SARS-CoV-2 - metabolism
Viral Nonstructural Proteins - genetics
Viral Nonstructural Proteins - metabolism
Virus Replication
ISSN:1096-0341, 1096-0341
Online Access:Get more information
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Summary:We biochemically simulated the mutation synthesis process of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) complex (nsp7/nsp8/nsp12) involving two sequential mechanistic steps that occur during genomic replication: misinsertion (incorporation of incorrect nucleotides) and mismatch extension. Then, we also simulated mismatch repair process catalyzed by the viral nsp10/nsp14 ExoN complex. In these mechanistic simulations, while SARS-CoV-2 RdRp displays efficient mutation synthesis capability, the viral ExoN complex was able to effectively repair the mismatch primers generated during the mutation synthesis. Also, we observed that the delayed RNA synthesis induced by mutation synthesis process was rescued by the viral ExoN activity. Collectively, our biochemical simulations suggest that SARS-CoV-2 ExoN complex may contribute to both maintenance of proper viral genetic diversity levels and successful completion of the viral large RNA genome replication by removing mismatches generated by the viral RdRp.
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ISSN:1096-0341
1096-0341
DOI:10.1016/j.virol.2024.110255