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The coronavirus proofreading exoribonuclease mediates extensive viral recombination

Jennifer Gribble, Andrea J. Pruijssers, Maria L. Agostini, Jordan Anderson-Daniels, James D. Chappell, Xiaotao Lu, Laura J. Stevens, View ORCID ProfileAndrew L. Routh, Mark R. Denison
doi: https://doi.org/10.1101/2020.04.23.057786
Jennifer Gribble
1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
3Vanderbilt Institute for Infection, Immunology, and Inflammation (VI4), Vanderbilt University Medical Center, Nashville, TN, USA
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Andrea J. Pruijssers
2Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
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Maria L. Agostini
2Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
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Jordan Anderson-Daniels
2Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
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James D. Chappell
2Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
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Xiaotao Lu
2Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
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Laura J. Stevens
2Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
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Andrew L. Routh
4Department of Biochemistry and Molecular Biology, University of Texas – Medical Branch, Galveston, TX, USA
5Sealy Center for Structural Biology and Molecular Biophysics, University of Texas – Medical Branch, Galveston, TX, USA
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  • For correspondence: mark.denison@vumc.org alrouth@utmb.edu
Mark R. Denison
1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
2Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
3Vanderbilt Institute for Infection, Immunology, and Inflammation (VI4), Vanderbilt University Medical Center, Nashville, TN, USA
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  • For correspondence: mark.denison@vumc.org alrouth@utmb.edu
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SUMMARY

Coronaviruses (CoVs) emerge as zoonoses and cause severe disease in humans, demonstrated by the SARS-CoV-2 (COVID-19) pandemic. RNA recombination is required during normal CoV replication for subgenomic mRNA (sgmRNA) synthesis and generates defective viral genomes (DVGs) of unknown function. However, the determinants and patterns of CoV recombination are unknown. Here, we show that divergent β-CoVs SARS-CoV-2, MERS-CoV, and murine hepatitis virus (MHV) perform extensive RNA recombination in culture, generating similar patterns of recombination junctions and diverse populations of DVGs and sgmRNAs. We demonstrate that the CoV proofreading nonstructural protein (nsp14) 3’-to-5’ exoribonuclease (nsp14-ExoN) is required for normal CoV recombination and that its genetic inactivation causes significantly decreased frequency and altered patterns of recombination in both infected cells and released virions. Thus, nsp14-ExoN is a key determinant of both high fidelity CoV replication and recombination, and thereby represents a highly-conserved and vulnerable target for virus inhibition and attenuation.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵# Lead Contact: M.R.D: mark.denison{at}vumc.org

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted April 25, 2020.
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The coronavirus proofreading exoribonuclease mediates extensive viral recombination
Jennifer Gribble, Andrea J. Pruijssers, Maria L. Agostini, Jordan Anderson-Daniels, James D. Chappell, Xiaotao Lu, Laura J. Stevens, Andrew L. Routh, Mark R. Denison
bioRxiv 2020.04.23.057786; doi: https://doi.org/10.1101/2020.04.23.057786
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The coronavirus proofreading exoribonuclease mediates extensive viral recombination
Jennifer Gribble, Andrea J. Pruijssers, Maria L. Agostini, Jordan Anderson-Daniels, James D. Chappell, Xiaotao Lu, Laura J. Stevens, Andrew L. Routh, Mark R. Denison
bioRxiv 2020.04.23.057786; doi: https://doi.org/10.1101/2020.04.23.057786

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