The coronavirus proofreading exoribonuclease mediates extensive viral recombination
Recombination is proposed to be critical for coronavirus (CoV) diversity and emergence of SARS-CoV-2 and other zoonotic CoVs. While RNA recombination is required during normal CoV replication, the mechanisms and determinants of CoV recombination are not known. CoVs encode an RNA proofreading exoribonuclease (nsp14-ExoN) that is distinct from the CoV polymerase and is responsible for high-fidelity RNA synthesis, resistance to nucleoside analogues, immune evasion, and virulence. Here, we demonstrate that CoVs, including SARS-CoV-2, MERS-CoV, and the model CoV murine hepatitis virus (MHV), generate extensive and diverse recombination products during replication in culture. We show that the MHV nsp14-ExoN is required for native recombination, and that inactivation of ExoN results in decreased recombination frequency and altered recombination products. These results add yet another critical function to nsp14-ExoN, highlight the uniqueness of the evolved coronavirus replicase, and further emphasize nsp14-ExoN as a central, completely conserved, and vulnerable target for inhibitors and attenuation of SARS-CoV-2 and future emerging zoonotic CoVs.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:17 |
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| Enthalten in: |
PLoS pathogens - 17(2021), 1 vom: 26. Jan., Seite e1009226 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Gribble, Jennifer [VerfasserIn] |
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| Links: |
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| Themen: |
Antiviral Agents |
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| Anmerkungen: |
Date Completed 17.02.2021 Date Revised 16.02.2024 published: Electronic-eCollection Citation Status MEDLINE |
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| doi: |
10.1371/journal.ppat.1009226 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM320275752 |
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| 245 | 1 | 4 | |a The coronavirus proofreading exoribonuclease mediates extensive viral recombination |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Recombination is proposed to be critical for coronavirus (CoV) diversity and emergence of SARS-CoV-2 and other zoonotic CoVs. While RNA recombination is required during normal CoV replication, the mechanisms and determinants of CoV recombination are not known. CoVs encode an RNA proofreading exoribonuclease (nsp14-ExoN) that is distinct from the CoV polymerase and is responsible for high-fidelity RNA synthesis, resistance to nucleoside analogues, immune evasion, and virulence. Here, we demonstrate that CoVs, including SARS-CoV-2, MERS-CoV, and the model CoV murine hepatitis virus (MHV), generate extensive and diverse recombination products during replication in culture. We show that the MHV nsp14-ExoN is required for native recombination, and that inactivation of ExoN results in decreased recombination frequency and altered recombination products. These results add yet another critical function to nsp14-ExoN, highlight the uniqueness of the evolved coronavirus replicase, and further emphasize nsp14-ExoN as a central, completely conserved, and vulnerable target for inhibitors and attenuation of SARS-CoV-2 and future emerging zoonotic CoVs | ||
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| 700 | 1 | |a Stevens, Laura J |e verfasserin |4 aut | |
| 700 | 1 | |a Agostini, Maria L |e verfasserin |4 aut | |
| 700 | 1 | |a Anderson-Daniels, Jordan |e verfasserin |4 aut | |
| 700 | 1 | |a Chappell, James D |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Xiaotao |e verfasserin |4 aut | |
| 700 | 1 | |a Pruijssers, Andrea J |e verfasserin |4 aut | |
| 700 | 1 | |a Routh, Andrew L |e verfasserin |4 aut | |
| 700 | 1 | |a Denison, Mark R |e verfasserin |4 aut | |
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