{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T07:46:46Z","timestamp":1792136806463,"version":"4.4.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1009226","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,1,29]],"date-time":"2021-01-29T00:00:00Z","timestamp":1611878400000}}],"reference-count":72,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T00:00:00Z","timestamp":1611014400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI108197"],"award-info":[{"award-number":["R01AI108197"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32GM065086"],"award-info":[{"award-number":["T32GM065086"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["F31AI133952"],"award-info":[{"award-number":["F31AI133952"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Dolly Parton COVID-19 Research Fund"},{"DOI":"10.13039\/100006538","name":"School of Medicine, Vanderbilt University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006538","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009226","type":"journal-article","created":{"date-parts":[[2021,1,19]],"date-time":"2021-01-19T13:51:22Z","timestamp":1611064282000},"page":"e1009226","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":270,"title":["The coronavirus proofreading exoribonuclease mediates extensive viral recombination"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0815-5798","authenticated-orcid":true,"given":"Jennifer","family":"Gribble","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura J.","family":"Stevens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria L.","family":"Agostini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9275-4330","authenticated-orcid":true,"given":"Jordan","family":"Anderson-Daniels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James D.","family":"Chappell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaotao","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7910-626X","authenticated-orcid":true,"given":"Andrea J.","family":"Pruijssers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2874-5990","authenticated-orcid":true,"given":"Andrew L.","family":"Routh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2655-0900","authenticated-orcid":true,"given":"Mark R.","family":"Denison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,1,19]]},"reference":[{"key":"ppat.1009226.ref001","first-page":"1","article-title":"A new coronavirus associated with human respiratory disease in China","author":"F Wu","year":"2020","journal-title":"Nature"},{"key":"ppat.1009226.ref002","article-title":"Recombination and lineage-specific mutations led to the emergence of SARS-CoV-2","author":"J\u00c1 Pati\u00f1o-Galindo","year":"2020","journal-title":"bioRxiv"},{"key":"ppat.1009226.ref003","article-title":"Evidence of the Recombinant Origin and Ongoing Mutations in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)","author":"J-M Huang","year":"2020","journal-title":"bioRxiv"},{"key":"ppat.1009226.ref004","article-title":"Emergence of SARS-CoV-2 through Recombination and Strong Purifying Selection","author":"X Li","year":"2020","journal-title":"bioRxiv"},{"key":"ppat.1009226.ref005","article-title":"2019 novel coronavirus is undergoing active recombination","author":"H. 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Eckerle","year":"2007","journal-title":"Journal of Virology"},{"issue":"5","key":"ppat.1009226.ref035","doi-asserted-by":"crossref","first-page":"e1000896","DOI":"10.1371\/journal.ppat.1000896","article-title":"Infidelity of SARS-CoV Nsp14-exonuclease mutant virus replication is revealed by complete genome sequencing","volume":"6","author":"LD Eckerle","year":"2010","journal-title":"PLoS pathogens"},{"issue":"2","key":"ppat.1009226.ref036","doi-asserted-by":"crossref","first-page":"E162","DOI":"10.1073\/pnas.1718806115","article-title":"Structural and molecular basis of mismatch correction and ribavirin excision from coronavirus RNA","volume":"115","author":"F Ferron","year":"2018","journal-title":"Proc Natl Acad Sci USA"},{"issue":"30","key":"ppat.1009226.ref037","doi-asserted-by":"crossref","first-page":"9436","DOI":"10.1073\/pnas.1508686112","article-title":"Structural basis and functional analysis of the SARS coronavirus nsp14\u2013nsp10 complex","volume":"112","author":"Y 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Case","year":"2017","journal-title":"J Virol"},{"issue":"2","key":"ppat.1009226.ref044","doi-asserted-by":"crossref","first-page":"e11","DOI":"10.1093\/nar\/gkt916","article-title":"Discovery of functional genomic motifs in viruses with ViReMa\u2013a Virus Recombination Mapper\u2013for analysis of next-generation sequencing data","volume":"42","author":"A Routh","year":"2014","journal-title":"Nucleic Acids Res"},{"issue":"4","key":"ppat.1009226.ref045","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1016\/j.cell.2020.04.011","article-title":"The Architecture of SARS-CoV-2 Transcriptome","volume":"181","author":"D Kim","year":"2020","journal-title":"Cell"},{"issue":"6","key":"ppat.1009226.ref046","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.00473-12","article-title":"Genomic characterization of a newly discovered coronavirus associated with acute respiratory distress syndrome in humans","volume":"3","author":"S van 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