Coronaviruses Lacking Exoribonuclease Activity Are Susceptible to Lethal Mutagenesis: Evidence for Proofreading and Potential Therapeutics
Identifieur interne : 000161 ( France/Analysis ); précédent : 000160; suivant : 000162Coronaviruses Lacking Exoribonuclease Activity Are Susceptible to Lethal Mutagenesis: Evidence for Proofreading and Potential Therapeutics
Auteurs : Everett Clinton Smith [États-Unis] ; Hervé Blanc [France] ; Marco Vignuzzi [France] ; Mark R. Denison [États-Unis]Source :
- PLoS Pathogens [ 1553-7366 ] ; 2013.
Descripteurs français
- KwdFr :
- ARN messager (génétique), ARN viral (génétique), ARN viral (métabolisme), Animaux, Antiviraux (pharmacologie), Apoptose (), Astrocytome (métabolisme), Astrocytome (traitement médicamenteux), Astrocytome (virologie), Cellules cancéreuses en culture, Coronavirus (), Coronavirus (enzymologie), Coronavirus (génétique), Exoribonucleases (génétique), Exoribonucleases (métabolisme), Génome viral, Humains, Infections à coronavirus (génétique), Infections à coronavirus (traitement médicamenteux), Infections à coronavirus (virologie), Mutagenèse (génétique), Mutagènes (pharmacologie), Mutation (génétique), Prolifération cellulaire (), Protéines virales (génétique), Protéines virales (métabolisme), RT-PCR, Réaction de polymérisation en chaine en temps réel, Réplication virale (), Souris, Tumeurs du cerveau (métabolisme), Tumeurs du cerveau (traitement médicamenteux), Tumeurs du cerveau (virologie).
- MESH :
- enzymologie : Coronavirus.
- génétique : ARN messager, ARN viral, Coronavirus, Exoribonucleases, Infections à coronavirus, Mutagenèse, Mutation, Protéines virales.
- métabolisme : ARN viral, Astrocytome, Exoribonucleases, Protéines virales, Tumeurs du cerveau.
- pharmacologie : Antiviraux, Mutagènes.
- traitement médicamenteux : Astrocytome, Infections à coronavirus, Tumeurs du cerveau.
- virologie : Astrocytome, Infections à coronavirus, Tumeurs du cerveau.
- Animaux, Apoptose, Cellules cancéreuses en culture, Coronavirus, Génome viral, Humains, Prolifération cellulaire, RT-PCR, Réaction de polymérisation en chaine en temps réel, Réplication virale, Souris.
English descriptors
- KwdEn :
- Animals, Antiviral Agents (pharmacology), Apoptosis (drug effects), Astrocytoma (drug therapy), Astrocytoma (metabolism), Astrocytoma (virology), Brain Neoplasms (drug therapy), Brain Neoplasms (metabolism), Brain Neoplasms (virology), Cell Proliferation (drug effects), Coronavirus (drug effects), Coronavirus (enzymology), Coronavirus (genetics), Coronavirus Infections (drug therapy), Coronavirus Infections (genetics), Coronavirus Infections (virology), Exoribonucleases (genetics), Exoribonucleases (metabolism), Genome, Viral, Humans, Mice, Mutagenesis (genetics), Mutagens (pharmacology), Mutation (genetics), RNA, Messenger (genetics), RNA, Viral (genetics), RNA, Viral (metabolism), Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured, Viral Proteins (genetics), Viral Proteins (metabolism), Virus Replication (drug effects).
- MESH :
- chemical , genetics : Exoribonucleases, RNA, Messenger, RNA, Viral, Viral Proteins.
- chemical , metabolism : Exoribonucleases, RNA, Viral, Viral Proteins.
- chemical , pharmacology : Antiviral Agents, Mutagens.
- drug effects : Apoptosis, Cell Proliferation, Coronavirus, Virus Replication.
- drug therapy : Astrocytoma, Brain Neoplasms, Coronavirus Infections.
- enzymology : Coronavirus.
- genetics : Coronavirus, Coronavirus Infections, Mutagenesis, Mutation.
- metabolism : Astrocytoma, Brain Neoplasms.
- virology : Astrocytoma, Brain Neoplasms, Coronavirus Infections.
- Animals, Genome, Viral, Humans, Mice, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Tumor Cells, Cultured.
Abstract
No therapeutics or vaccines currently exist for human coronaviruses (HCoVs). The Severe Acute Respiratory Syndrome-associated coronavirus (SARS-CoV) epidemic in 2002–2003, and the recent emergence of Middle East Respiratory Syndrome coronavirus (MERS-CoV) in April 2012, emphasize the high probability of future zoonotic HCoV emergence causing severe and lethal human disease. Additionally, the resistance of SARS-CoV to ribavirin (RBV) demonstrates the need to define new targets for inhibition of CoV replication. CoVs express a 3′-to-5′ exoribonuclease in nonstructural protein 14 (nsp14-ExoN) that is required for high-fidelity replication and is conserved across the CoV family. All genetic and biochemical data support the hypothesis that nsp14-ExoN has an RNA proofreading function. Thus, we hypothesized that ExoN is responsible for CoV resistance to RNA mutagens. We demonstrate that while wild-type (ExoN+) CoVs were resistant to RBV and 5-fluorouracil (5-FU), CoVs lacking ExoN activity (ExoN−) were up to 300-fold more sensitive. While the primary antiviral activity of RBV against CoVs was not mutagenesis, ExoN− CoVs treated with 5-FU demonstrated both enhanced sensitivity during multi-cycle replication, as well as decreased specific infectivity, consistent with 5-FU functioning as a mutagen. Comparison of full-genome next-generation sequencing of 5-FU treated SARS-CoV populations revealed a 16-fold increase in the number of mutations within the ExoN− population as compared to ExoN+. Ninety percent of these mutations represented A:G and U:C transitions, consistent with 5-FU incorporation during RNA synthesis. Together our results constitute direct evidence that CoV ExoN activity provides a critical proofreading function during virus replication. Furthermore, these studies identify ExoN as the first viral protein distinct from the RdRp that determines the sensitivity of RNA viruses to mutagens. Finally, our results show the importance of ExoN as a target for inhibition, and suggest that small-molecule inhibitors of ExoN activity could be potential pan-CoV therapeutics in combination with RBV or RNA mutagens.
Url:
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744431
- https://hal-pasteur.archives-ouvertes.fr/pasteur-00918207
DOI: 10.1371/journal.ppat.1003565
PubMed: 23966862
PubMed Central: 3744431
Affiliations:
Links toward previous steps (curation, corpus...)
- to stream Pmc, to step Corpus: 001407
- to stream Pmc, to step Curation: 001407
- to stream Pmc, to step Checkpoint: 000A00
- to stream PubMed, to step Corpus: 001145
- to stream PubMed, to step Curation: 001145
- to stream PubMed, to step Checkpoint: 001206
- to stream Ncbi, to step Merge: 002732
- to stream Ncbi, to step Curation: 002732
- to stream Ncbi, to step Checkpoint: 002732
- to stream Hal, to step Corpus: 000039
- to stream Hal, to step Curation: 000039
- to stream Hal, to step Checkpoint: 000102
- to stream Main, to step Merge: 001979
- to stream Main, to step Curation: 001970
- to stream Main, to step Exploration: 001970
- to stream France, to step Extraction: 000161
Links to Exploration step
PMC:3744431Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Coronaviruses Lacking Exoribonuclease Activity Are Susceptible to Lethal Mutagenesis: Evidence for Proofreading and Potential Therapeutics</title><author><name sortKey="Smith, Everett Clinton" sort="Smith, Everett Clinton" uniqKey="Smith E" first="Everett Clinton" last="Smith">Everett Clinton Smith</name><affiliation wicri:level="2"><nlm:aff id="aff1"><addr-line>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="aff2"><addr-line>The Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, Tennessee</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Blanc, Herve" sort="Blanc, Herve" uniqKey="Blanc H" first="Hervé" last="Blanc">Hervé Blanc</name><affiliation wicri:level="3"><nlm:aff id="aff3"><addr-line>Institut Pasteur, Centre National de la Recherche Scientifique Unité de Recherche Associée 3015, Paris, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut Pasteur, Centre National de la Recherche Scientifique Unité de Recherche Associée 3015, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Vignuzzi, Marco" sort="Vignuzzi, Marco" uniqKey="Vignuzzi M" first="Marco" last="Vignuzzi">Marco Vignuzzi</name><affiliation wicri:level="3"><nlm:aff id="aff3"><addr-line>Institut Pasteur, Centre National de la Recherche Scientifique Unité de Recherche Associée 3015, Paris, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut Pasteur, Centre National de la Recherche Scientifique Unité de Recherche Associée 3015, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Denison, Mark R" sort="Denison, Mark R" uniqKey="Denison M" first="Mark R." last="Denison">Mark R. Denison</name><affiliation wicri:level="2"><nlm:aff id="aff1"><addr-line>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="aff2"><addr-line>The Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, Tennessee</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="aff4"><addr-line>Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">23966862</idno><idno type="pmc">3744431</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744431</idno><idno type="RBID">PMC:3744431</idno><idno type="doi">10.1371/journal.ppat.1003565</idno><date when="2013">2013</date><idno type="wicri:Area/Pmc/Corpus">001407</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001407</idno><idno type="wicri:Area/Pmc/Curation">001407</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">001407</idno><idno type="wicri:Area/Pmc/Checkpoint">000A00</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000A00</idno><idno type="wicri:source">PubMed</idno><idno type="RBID">pubmed:23966862</idno><idno type="wicri:Area/PubMed/Corpus">001145</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001145</idno><idno type="wicri:Area/PubMed/Curation">001145</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001145</idno><idno type="wicri:Area/PubMed/Checkpoint">001206</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">001206</idno><idno type="wicri:Area/Ncbi/Merge">002732</idno><idno type="wicri:Area/Ncbi/Curation">002732</idno><idno type="wicri:Area/Ncbi/Checkpoint">002732</idno><idno type="wicri:doubleKey">1553-7366:2013:Smith E:coronaviruses:lacking:exoribonuclease</idno><idno type="wicri:source">HAL</idno><idno type="RBID">Hal:pasteur-00918207</idno><idno type="url">https://hal-pasteur.archives-ouvertes.fr/pasteur-00918207</idno><idno type="wicri:Area/Hal/Corpus">000039</idno><idno type="wicri:Area/Hal/Curation">000039</idno><idno type="wicri:Area/Hal/Checkpoint">000102</idno><idno type="wicri:explorRef" wicri:stream="Hal" wicri:step="Checkpoint">000102</idno><idno type="wicri:doubleKey">1553-7366:2013:Smith E:coronaviruses:lacking:exoribonuclease</idno><idno type="wicri:Area/Main/Merge">001979</idno><idno type="wicri:Area/Main/Curation">001970</idno><idno type="wicri:Area/Main/Exploration">001970</idno><idno type="wicri:Area/France/Extraction">000161</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Coronaviruses Lacking Exoribonuclease Activity Are Susceptible to Lethal Mutagenesis: Evidence for Proofreading and Potential Therapeutics</title><author><name sortKey="Smith, Everett Clinton" sort="Smith, Everett Clinton" uniqKey="Smith E" first="Everett Clinton" last="Smith">Everett Clinton Smith</name><affiliation wicri:level="2"><nlm:aff id="aff1"><addr-line>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="aff2"><addr-line>The Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, Tennessee</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author><author><name sortKey="Blanc, Herve" sort="Blanc, Herve" uniqKey="Blanc H" first="Hervé" last="Blanc">Hervé Blanc</name><affiliation wicri:level="3"><nlm:aff id="aff3"><addr-line>Institut Pasteur, Centre National de la Recherche Scientifique Unité de Recherche Associée 3015, Paris, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut Pasteur, Centre National de la Recherche Scientifique Unité de Recherche Associée 3015, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Vignuzzi, Marco" sort="Vignuzzi, Marco" uniqKey="Vignuzzi M" first="Marco" last="Vignuzzi">Marco Vignuzzi</name><affiliation wicri:level="3"><nlm:aff id="aff3"><addr-line>Institut Pasteur, Centre National de la Recherche Scientifique Unité de Recherche Associée 3015, Paris, France</addr-line></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea>Institut Pasteur, Centre National de la Recherche Scientifique Unité de Recherche Associée 3015, Paris</wicri:regionArea><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation></author><author><name sortKey="Denison, Mark R" sort="Denison, Mark R" uniqKey="Denison M" first="Mark R." last="Denison">Mark R. Denison</name><affiliation wicri:level="2"><nlm:aff id="aff1"><addr-line>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="aff2"><addr-line>The Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>The Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University Medical Center, Nashville, Tennessee</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="aff4"><addr-line>Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America</addr-line></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee</wicri:regionArea><placeName><region type="state">Tennessee</region></placeName></affiliation></author></analytic><series><title level="j">PLoS Pathogens</title><idno type="ISSN">1553-7366</idno><idno type="eISSN">1553-7374</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Antiviral Agents (pharmacology)</term><term>Apoptosis (drug effects)</term><term>Astrocytoma (drug therapy)</term><term>Astrocytoma (metabolism)</term><term>Astrocytoma (virology)</term><term>Brain Neoplasms (drug therapy)</term><term>Brain Neoplasms (metabolism)</term><term>Brain Neoplasms (virology)</term><term>Cell Proliferation (drug effects)</term><term>Coronavirus (drug effects)</term><term>Coronavirus (enzymology)</term><term>Coronavirus (genetics)</term><term>Coronavirus Infections (drug therapy)</term><term>Coronavirus Infections (genetics)</term><term>Coronavirus Infections (virology)</term><term>Exoribonucleases (genetics)</term><term>Exoribonucleases (metabolism)</term><term>Genome, Viral</term><term>Humans</term><term>Mice</term><term>Mutagenesis (genetics)</term><term>Mutagens (pharmacology)</term><term>Mutation (genetics)</term><term>RNA, Messenger (genetics)</term><term>RNA, Viral (genetics)</term><term>RNA, Viral (metabolism)</term><term>Real-Time Polymerase Chain Reaction</term><term>Reverse Transcriptase Polymerase Chain Reaction</term><term>Tumor Cells, Cultured</term><term>Viral Proteins (genetics)</term><term>Viral Proteins (metabolism)</term><term>Virus Replication (drug effects)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>ARN messager (génétique)</term><term>ARN viral (génétique)</term><term>ARN viral (métabolisme)</term><term>Animaux</term><term>Antiviraux (pharmacologie)</term><term>Apoptose ()</term><term>Astrocytome (métabolisme)</term><term>Astrocytome (traitement médicamenteux)</term><term>Astrocytome (virologie)</term><term>Cellules cancéreuses en culture</term><term>Coronavirus ()</term><term>Coronavirus (enzymologie)</term><term>Coronavirus (génétique)</term><term>Exoribonucleases (génétique)</term><term>Exoribonucleases (métabolisme)</term><term>Génome viral</term><term>Humains</term><term>Infections à coronavirus (génétique)</term><term>Infections à coronavirus (traitement médicamenteux)</term><term>Infections à coronavirus (virologie)</term><term>Mutagenèse (génétique)</term><term>Mutagènes (pharmacologie)</term><term>Mutation (génétique)</term><term>Prolifération cellulaire ()</term><term>Protéines virales (génétique)</term><term>Protéines virales (métabolisme)</term><term>RT-PCR</term><term>Réaction de polymérisation en chaine en temps réel</term><term>Réplication virale ()</term><term>Souris</term><term>Tumeurs du cerveau (métabolisme)</term><term>Tumeurs du cerveau (traitement médicamenteux)</term><term>Tumeurs du cerveau (virologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Exoribonucleases</term><term>RNA, Messenger</term><term>RNA, Viral</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Exoribonucleases</term><term>RNA, Viral</term><term>Viral Proteins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Antiviral Agents</term><term>Mutagens</term></keywords><keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Apoptosis</term><term>Cell Proliferation</term><term>Coronavirus</term><term>Virus Replication</term></keywords><keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Astrocytoma</term><term>Brain Neoplasms</term><term>Coronavirus Infections</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Coronavirus</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Coronavirus</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Coronavirus</term><term>Coronavirus Infections</term><term>Mutagenesis</term><term>Mutation</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>ARN messager</term><term>ARN viral</term><term>Coronavirus</term><term>Exoribonucleases</term><term>Infections à coronavirus</term><term>Mutagenèse</term><term>Mutation</term><term>Protéines virales</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Astrocytoma</term><term>Brain Neoplasms</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>ARN viral</term><term>Astrocytome</term><term>Exoribonucleases</term><term>Protéines virales</term><term>Tumeurs du cerveau</term></keywords><keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antiviraux</term><term>Mutagènes</term></keywords><keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Astrocytome</term><term>Infections à coronavirus</term><term>Tumeurs du cerveau</term></keywords><keywords scheme="MESH" qualifier="virologie" xml:lang="fr"><term>Astrocytome</term><term>Infections à coronavirus</term><term>Tumeurs du cerveau</term></keywords><keywords scheme="MESH" qualifier="virology" xml:lang="en"><term>Astrocytoma</term><term>Brain Neoplasms</term><term>Coronavirus Infections</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Genome, Viral</term><term>Humans</term><term>Mice</term><term>Real-Time Polymerase Chain Reaction</term><term>Reverse Transcriptase Polymerase Chain Reaction</term><term>Tumor Cells, Cultured</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Apoptose</term><term>Cellules cancéreuses en culture</term><term>Coronavirus</term><term>Génome viral</term><term>Humains</term><term>Prolifération cellulaire</term><term>RT-PCR</term><term>Réaction de polymérisation en chaine en temps réel</term><term>Réplication virale</term><term>Souris</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>No therapeutics or vaccines currently exist for human coronaviruses (HCoVs). The Severe Acute Respiratory Syndrome-associated coronavirus (SARS-CoV) epidemic in 2002–2003, and the recent emergence of Middle East Respiratory Syndrome coronavirus (MERS-CoV) in April 2012, emphasize the high probability of future zoonotic HCoV emergence causing severe and lethal human disease. Additionally, the resistance of SARS-CoV to ribavirin (RBV) demonstrates the need to define new targets for inhibition of CoV replication. CoVs express a 3′-to-5′ exoribonuclease in nonstructural protein 14 (nsp14-ExoN) that is required for high-fidelity replication and is conserved across the CoV family. All genetic and biochemical data support the hypothesis that nsp14-ExoN has an RNA proofreading function. Thus, we hypothesized that ExoN is responsible for CoV resistance to RNA mutagens. We demonstrate that while wild-type (ExoN+) CoVs were resistant to RBV and 5-fluorouracil (5-FU), CoVs lacking ExoN activity (ExoN−) were up to 300-fold more sensitive. While the primary antiviral activity of RBV against CoVs was not mutagenesis, ExoN− CoVs treated with 5-FU demonstrated both enhanced sensitivity during multi-cycle replication, as well as decreased specific infectivity, consistent with 5-FU functioning as a mutagen. Comparison of full-genome next-generation sequencing of 5-FU treated SARS-CoV populations revealed a 16-fold increase in the number of mutations within the ExoN− population as compared to ExoN+. Ninety percent of these mutations represented A:G and U:C transitions, consistent with 5-FU incorporation during RNA synthesis. Together our results constitute direct evidence that CoV ExoN activity provides a critical proofreading function during virus replication. Furthermore, these studies identify ExoN as the first viral protein distinct from the RdRp that determines the sensitivity of RNA viruses to mutagens. Finally, our results show the importance of ExoN as a target for inhibition, and suggest that small-molecule inhibitors of ExoN activity could be potential pan-CoV therapeutics in combination with RBV or RNA mutagens.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Zaki, Am" uniqKey="Zaki A">AM Zaki</name></author><author><name sortKey="Van Boheemen, S" uniqKey="Van Boheemen S">S van Boheemen</name></author><author><name sortKey="Bestebroer, Tm" uniqKey="Bestebroer T">TM Bestebroer</name></author><author><name sortKey="Osterhaus, Ad" uniqKey="Osterhaus A">AD Osterhaus</name></author><author><name sortKey="Fouchier, Ra" uniqKey="Fouchier R">RA Fouchier</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Perlman, S" uniqKey="Perlman S">S Perlman</name></author><author><name sortKey="Netland, J" uniqKey="Netland J">J Netland</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Drosten, C" uniqKey="Drosten C">C Drosten</name></author><author><name sortKey="Gunther, S" uniqKey="Gunther S">S Gunther</name></author><author><name sortKey="Preiser, W" uniqKey="Preiser W">W Preiser</name></author><author><name sortKey="Van Der Werf, S" uniqKey="Van Der Werf S">S van der Werf</name></author><author><name sortKey="Brodt, Hr" uniqKey="Brodt H">HR Brodt</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ksiazek, Tg" uniqKey="Ksiazek T">TG Ksiazek</name></author><author><name sortKey="Erdman, D" uniqKey="Erdman D">D Erdman</name></author><author><name sortKey="Goldsmith, Cs" uniqKey="Goldsmith C">CS Goldsmith</name></author><author><name sortKey="Zaki, Sr" uniqKey="Zaki S">SR Zaki</name></author><author><name sortKey="Peret, T" uniqKey="Peret T">T Peret</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Peiris, Jsm" uniqKey="Peiris J">JSM Peiris</name></author><author><name sortKey="Lai, St" uniqKey="Lai S">ST Lai</name></author><author><name sortKey="Poon, Llm" uniqKey="Poon L">LLM Poon</name></author><author><name sortKey="Guan, Y" uniqKey="Guan Y">Y Guan</name></author><author><name sortKey="Yam, Lyc" uniqKey="Yam L">LYC Yam</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Vijaykrishna, D" uniqKey="Vijaykrishna D">D Vijaykrishna</name></author><author><name sortKey="Smith, Gj" uniqKey="Smith G">GJ Smith</name></author><author><name sortKey="Zhang, Jx" uniqKey="Zhang J">JX Zhang</name></author><author><name sortKey="Peiris, Js" uniqKey="Peiris J">JS Peiris</name></author><author><name sortKey="Chen, H" uniqKey="Chen H">H Chen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pfefferle, S" uniqKey="Pfefferle S">S Pfefferle</name></author><author><name sortKey="Oppong, S" uniqKey="Oppong S">S Oppong</name></author><author><name sortKey="Drexler, Jf" uniqKey="Drexler J">JF Drexler</name></author><author><name sortKey="Gloza Rausch, F" uniqKey="Gloza Rausch F">F Gloza-Rausch</name></author><author><name sortKey="Ipsen, A" uniqKey="Ipsen A">A Ipsen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gloza Rausch, F" uniqKey="Gloza Rausch F">F Gloza-Rausch</name></author><author><name sortKey="Ipsen, A" uniqKey="Ipsen A">A Ipsen</name></author><author><name sortKey="Seebens, A" uniqKey="Seebens A">A Seebens</name></author><author><name sortKey="Gottsche, M" uniqKey="Gottsche M">M Gottsche</name></author><author><name sortKey="Panning, M" uniqKey="Panning M">M Panning</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Huynh, J" uniqKey="Huynh J">J Huynh</name></author><author><name sortKey="Li, S" uniqKey="Li S">S Li</name></author><author><name sortKey="Yount, B" uniqKey="Yount B">B Yount</name></author><author><name sortKey="Smith, A" uniqKey="Smith A">A Smith</name></author><author><name sortKey="Sturges, L" uniqKey="Sturges L">L Sturges</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Boheemen, S" uniqKey="Van Boheemen S">S van Boheemen</name></author><author><name sortKey="De Graaf, M" uniqKey="De Graaf M">M de Graaf</name></author><author><name sortKey="Lauber, C" uniqKey="Lauber C">C Lauber</name></author><author><name sortKey="Bestebroer, Tm" uniqKey="Bestebroer T">TM Bestebroer</name></author><author><name sortKey="Raj, Vs" uniqKey="Raj V">VS Raj</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bermingham, A" uniqKey="Bermingham A">A Bermingham</name></author><author><name sortKey="Chand, Ma" uniqKey="Chand M">MA Chand</name></author><author><name sortKey="Brown, Cs" uniqKey="Brown C">CS Brown</name></author><author><name sortKey="Aarons, E" uniqKey="Aarons E">E Aarons</name></author><author><name sortKey="Tong, C" uniqKey="Tong C">C Tong</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Raj, Vs" uniqKey="Raj V">VS Raj</name></author><author><name sortKey="Mou, H" uniqKey="Mou H">H Mou</name></author><author><name sortKey="Smits, Sl" uniqKey="Smits S">SL Smits</name></author><author><name sortKey="Dekkers, Dh" uniqKey="Dekkers D">DH Dekkers</name></author><author><name sortKey="Muller, Ma" uniqKey="Muller M">MA Muller</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Minskaia, E" uniqKey="Minskaia E">E Minskaia</name></author><author><name sortKey="Hertzig, T" uniqKey="Hertzig T">T Hertzig</name></author><author><name sortKey="Gorbalenya, Ae" uniqKey="Gorbalenya A">AE Gorbalenya</name></author><author><name sortKey="Campanacci, V" uniqKey="Campanacci V">V Campanacci</name></author><author><name sortKey="Cambillau, C" uniqKey="Cambillau C">C Cambillau</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gorbalenya, Ae" uniqKey="Gorbalenya A">AE Gorbalenya</name></author><author><name sortKey="Enjuanes, L" uniqKey="Enjuanes L">L Enjuanes</name></author><author><name sortKey="Ziebuhr, J" uniqKey="Ziebuhr J">J Ziebuhr</name></author><author><name sortKey="Snijder, Ej" uniqKey="Snijder E">EJ Snijder</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Smith, Ec" uniqKey="Smith E">EC Smith</name></author><author><name sortKey="Denison, Mr" uniqKey="Denison M">MR Denison</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zuo, Y" uniqKey="Zuo Y">Y Zuo</name></author><author><name sortKey="Deutscher, Mp" uniqKey="Deutscher M">MP Deutscher</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Eckerle, Ld" uniqKey="Eckerle L">LD Eckerle</name></author><author><name sortKey="Becker, Mm" uniqKey="Becker M">MM Becker</name></author><author><name sortKey="Halpin, Ra" uniqKey="Halpin R">RA Halpin</name></author><author><name sortKey="Li, K" uniqKey="Li K">K Li</name></author><author><name sortKey="Venter, E" uniqKey="Venter E">E Venter</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Eckerle, Ld" uniqKey="Eckerle L">LD Eckerle</name></author><author><name sortKey="Lu, X" uniqKey="Lu X">X Lu</name></author><author><name sortKey="Sperry, Sm" uniqKey="Sperry S">SM Sperry</name></author><author><name sortKey="Choi, L" uniqKey="Choi L">L Choi</name></author><author><name sortKey="Denison, Mr" uniqKey="Denison M">MR Denison</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Graham, Rl" uniqKey="Graham R">RL Graham</name></author><author><name sortKey="Becker, Mm" uniqKey="Becker M">MM Becker</name></author><author><name sortKey="Eckerle, Ld" uniqKey="Eckerle L">LD Eckerle</name></author><author><name sortKey="Bolles, M" uniqKey="Bolles M">M Bolles</name></author><author><name sortKey="Denison, Mr" uniqKey="Denison M">MR Denison</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bouvet, M" uniqKey="Bouvet M">M Bouvet</name></author><author><name sortKey="Imbert, I" uniqKey="Imbert I">I Imbert</name></author><author><name sortKey="Subissi, L" uniqKey="Subissi L">L Subissi</name></author><author><name sortKey="Gluais, L" uniqKey="Gluais L">L Gluais</name></author><author><name sortKey="Canard, B" uniqKey="Canard B">B Canard</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Crotty, S" uniqKey="Crotty S">S Crotty</name></author><author><name sortKey="Cameron, Ce" uniqKey="Cameron C">CE Cameron</name></author><author><name sortKey="Andino, R" uniqKey="Andino R">R Andino</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Crotty, S" uniqKey="Crotty S">S Crotty</name></author><author><name sortKey="Maag, D" uniqKey="Maag D">D Maag</name></author><author><name sortKey="Arnold, Jj" uniqKey="Arnold J">JJ Arnold</name></author><author><name sortKey="Zhong, W" uniqKey="Zhong W">W Zhong</name></author><author><name sortKey="Lau, Jy" uniqKey="Lau J">JY Lau</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chiou, He" uniqKey="Chiou H">HE Chiou</name></author><author><name sortKey="Liu, Cl" uniqKey="Liu C">CL Liu</name></author><author><name sortKey="Buttrey, Mj" uniqKey="Buttrey M">MJ Buttrey</name></author><author><name sortKey="Kuo, Hp" uniqKey="Kuo H">HP Kuo</name></author><author><name sortKey="Liu, Hw" uniqKey="Liu H">HW Liu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Muller, Mp" uniqKey="Muller M">MP Muller</name></author><author><name sortKey="Dresser, L" uniqKey="Dresser L">L Dresser</name></author><author><name sortKey="Raboud, J" uniqKey="Raboud J">J Raboud</name></author><author><name sortKey="Mcgeer, A" uniqKey="Mcgeer A">A McGeer</name></author><author><name sortKey="Rea, E" uniqKey="Rea E">E Rea</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Barnard, Dl" uniqKey="Barnard D">DL Barnard</name></author><author><name sortKey="Day, Cw" uniqKey="Day C">CW Day</name></author><author><name sortKey="Bailey, K" uniqKey="Bailey K">K Bailey</name></author><author><name sortKey="Heiner, M" uniqKey="Heiner M">M Heiner</name></author><author><name sortKey="Montgomery, R" uniqKey="Montgomery R">R Montgomery</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Stockman, Lj" uniqKey="Stockman L">LJ Stockman</name></author><author><name sortKey="Bellamy, R" uniqKey="Bellamy R">R Bellamy</name></author><author><name sortKey="Garner, P" uniqKey="Garner P">P Garner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Grande Perez, A" uniqKey="Grande Perez A">A Grande-Perez</name></author><author><name sortKey="Sierra, S" uniqKey="Sierra S">S Sierra</name></author><author><name sortKey="Castro, Mg" uniqKey="Castro M">MG Castro</name></author><author><name sortKey="Domingo, E" uniqKey="Domingo E">E Domingo</name></author><author><name sortKey="Lowenstein, Pr" uniqKey="Lowenstein P">PR Lowenstein</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yount, B" uniqKey="Yount B">B Yount</name></author><author><name sortKey="Denison, Mr" uniqKey="Denison M">MR Denison</name></author><author><name sortKey="Weiss, Sr" uniqKey="Weiss S">SR Weiss</name></author><author><name sortKey="Baric, Rs" uniqKey="Baric R">RS Baric</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yount, B" uniqKey="Yount B">B Yount</name></author><author><name sortKey="Curtis, Km" uniqKey="Curtis K">KM Curtis</name></author><author><name sortKey="Fritz, Ea" uniqKey="Fritz E">EA Fritz</name></author><author><name sortKey="Hensley, Le" uniqKey="Hensley L">LE Hensley</name></author><author><name sortKey="Jahrling, Pb" uniqKey="Jahrling P">PB Jahrling</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Livak, Kj" uniqKey="Livak K">KJ Livak</name></author><author><name sortKey="Schmittgen, Td" uniqKey="Schmittgen T">TD Schmittgen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Donaldson, Ef" uniqKey="Donaldson E">EF Donaldson</name></author><author><name sortKey="Sims, Ac" uniqKey="Sims A">AC Sims</name></author><author><name sortKey="Graham, Rl" uniqKey="Graham R">RL Graham</name></author><author><name sortKey="Denison, Mr" uniqKey="Denison M">MR Denison</name></author><author><name sortKey="Baric, Rs" uniqKey="Baric R">RS Baric</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Donaldson, Ef" uniqKey="Donaldson E">EF Donaldson</name></author><author><name sortKey="Sims, Ac" uniqKey="Sims A">AC Sims</name></author><author><name sortKey="Deming, Dj" uniqKey="Deming D">DJ Deming</name></author><author><name sortKey="Baric, Rs" uniqKey="Baric R">RS Baric</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gnadig, Nf" uniqKey="Gnadig N">NF Gnadig</name></author><author><name sortKey="Beaucourt, S" uniqKey="Beaucourt S">S Beaucourt</name></author><author><name sortKey="Campagnola, G" uniqKey="Campagnola G">G Campagnola</name></author><author><name sortKey="Borderia, Av" uniqKey="Borderia A">AV Borderia</name></author><author><name sortKey="Sanz Ramos, M" uniqKey="Sanz Ramos M">M Sanz-Ramos</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, H" uniqKey="Li H">H Li</name></author><author><name sortKey="Durbin, R" uniqKey="Durbin R">R Durbin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Li, H" uniqKey="Li H">H Li</name></author><author><name sortKey="Handsaker, B" uniqKey="Handsaker B">B Handsaker</name></author><author><name sortKey="Wysoker, A" uniqKey="Wysoker A">A Wysoker</name></author><author><name sortKey="Fennell, T" uniqKey="Fennell T">T Fennell</name></author><author><name sortKey="Ruan, J" uniqKey="Ruan J">J Ruan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Crotty, S" uniqKey="Crotty S">S Crotty</name></author><author><name sortKey="Cameron, C" uniqKey="Cameron C">C Cameron</name></author><author><name sortKey="Andino, R" uniqKey="Andino R">R Andino</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Agudo, R" uniqKey="Agudo R">R Agudo</name></author><author><name sortKey="Ferrer Orta, C" uniqKey="Ferrer Orta C">C Ferrer-Orta</name></author><author><name sortKey="Arias, A" uniqKey="Arias A">A Arias</name></author><author><name sortKey="De La Higuera, I" uniqKey="De La Higuera I">I de la Higuera</name></author><author><name sortKey="Perales, C" uniqKey="Perales C">C Perales</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Arias, A" uniqKey="Arias A">A Arias</name></author><author><name sortKey="Arnold, Jj" uniqKey="Arnold J">JJ Arnold</name></author><author><name sortKey="Sierra, M" uniqKey="Sierra M">M Sierra</name></author><author><name sortKey="Smidansky, Ed" uniqKey="Smidansky E">ED Smidansky</name></author><author><name sortKey="Domingo, E" uniqKey="Domingo E">E Domingo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Maag, D" uniqKey="Maag D">D Maag</name></author><author><name sortKey="Castro, C" uniqKey="Castro C">C Castro</name></author><author><name sortKey="Hong, Z" uniqKey="Hong Z">Z Hong</name></author><author><name sortKey="Cameron, Ce" uniqKey="Cameron C">CE Cameron</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sierra, M" uniqKey="Sierra M">M Sierra</name></author><author><name sortKey="Airaksinen, A" uniqKey="Airaksinen A">A Airaksinen</name></author><author><name sortKey="Gonzalez Lopez, C" uniqKey="Gonzalez Lopez C">C Gonzalez-Lopez</name></author><author><name sortKey="Agudo, R" uniqKey="Agudo R">R Agudo</name></author><author><name sortKey="Arias, A" uniqKey="Arias A">A Arias</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kamiya, K" uniqKey="Kamiya K">K Kamiya</name></author><author><name sortKey="Huang, P" uniqKey="Huang P">P Huang</name></author><author><name sortKey="Plunkett, W" uniqKey="Plunkett W">W Plunkett</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lim, Se" uniqKey="Lim S">SE Lim</name></author><author><name sortKey="Copeland, Wc" uniqKey="Copeland W">WC Copeland</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Johnson, Aa" uniqKey="Johnson A">AA Johnson</name></author><author><name sortKey="Ray, As" uniqKey="Ray A">AS Ray</name></author><author><name sortKey="Hanes, J" uniqKey="Hanes J">J Hanes</name></author><author><name sortKey="Suo, Z" uniqKey="Suo Z">Z Suo</name></author><author><name sortKey="Colacino, Jm" uniqKey="Colacino J">JM Colacino</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, H" uniqKey="Lee H">H Lee</name></author><author><name sortKey="Hanes, J" uniqKey="Hanes J">J Hanes</name></author><author><name sortKey="Johnson, Ka" uniqKey="Johnson K">KA Johnson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Arnold, Jj" uniqKey="Arnold J">JJ Arnold</name></author><author><name sortKey="Sharma, Sd" uniqKey="Sharma S">SD Sharma</name></author><author><name sortKey="Feng, Jy" uniqKey="Feng J">JY Feng</name></author><author><name sortKey="Ray, As" uniqKey="Ray A">AS Ray</name></author><author><name sortKey="Smidansky, Ed" uniqKey="Smidansky E">ED Smidansky</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Coffey, Ll" uniqKey="Coffey L">LL Coffey</name></author><author><name sortKey="Beeharry, Y" uniqKey="Beeharry Y">Y Beeharry</name></author><author><name sortKey="Borderia, Av" uniqKey="Borderia A">AV Borderia</name></author><author><name sortKey="Blanc, H" uniqKey="Blanc H">H Blanc</name></author><author><name sortKey="Vignuzzi, M" uniqKey="Vignuzzi M">M Vignuzzi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vignuzzi, M" uniqKey="Vignuzzi M">M Vignuzzi</name></author><author><name sortKey="Wendt, E" uniqKey="Wendt E">E Wendt</name></author><author><name sortKey="Andino, R" uniqKey="Andino R">R Andino</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pfeiffer, Jk" uniqKey="Pfeiffer J">JK Pfeiffer</name></author><author><name sortKey="Kirkegaard, K" uniqKey="Kirkegaard K">K Kirkegaard</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Streeter, Dg" uniqKey="Streeter D">DG Streeter</name></author><author><name sortKey="Witkowski, Jt" uniqKey="Witkowski J">JT Witkowski</name></author><author><name sortKey="Khare, Gp" uniqKey="Khare G">GP Khare</name></author><author><name sortKey="Sidwell, Rw" uniqKey="Sidwell R">RW Sidwell</name></author><author><name sortKey="Bauer, Rj" uniqKey="Bauer R">RJ Bauer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Carter, Sb" uniqKey="Carter S">SB Carter</name></author><author><name sortKey="Franklin, Tj" uniqKey="Franklin T">TJ Franklin</name></author><author><name sortKey="Jones, Df" uniqKey="Jones D">DF Jones</name></author><author><name sortKey="Leonard, Bj" uniqKey="Leonard B">BJ Leonard</name></author><author><name sortKey="Mills, Sd" uniqKey="Mills S">SD Mills</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Carr, Sf" uniqKey="Carr S">SF Carr</name></author><author><name sortKey="Papp, E" uniqKey="Papp E">E Papp</name></author><author><name sortKey="Wu, Jc" uniqKey="Wu J">JC Wu</name></author><author><name sortKey="Natsumeda, Y" uniqKey="Natsumeda Y">Y Natsumeda</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Franklin, Tj" uniqKey="Franklin T">TJ Franklin</name></author><author><name sortKey="Cook, Jm" uniqKey="Cook J">JM Cook</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Takhampunya, R" uniqKey="Takhampunya R">R Takhampunya</name></author><author><name sortKey="Ubol, S" uniqKey="Ubol S">S Ubol</name></author><author><name sortKey="Houng, Hs" uniqKey="Houng H">HS Houng</name></author><author><name sortKey="Cameron, Ce" uniqKey="Cameron C">CE Cameron</name></author><author><name sortKey="Padmanabhan, R" uniqKey="Padmanabhan R">R Padmanabhan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Domingo, E" uniqKey="Domingo E">E Domingo</name></author><author><name sortKey="Sheldon, J" uniqKey="Sheldon J">J Sheldon</name></author><author><name sortKey="Perales, C" uniqKey="Perales C">C Perales</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ibarra, Kd" uniqKey="Ibarra K">KD Ibarra</name></author><author><name sortKey="Pfeiffer, Jk" uniqKey="Pfeiffer J">JK Pfeiffer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shah, Nr" uniqKey="Shah N">NR Shah</name></author><author><name sortKey="Sunderland, A" uniqKey="Sunderland A">A Sunderland</name></author><author><name sortKey="Grdzelishvili, Vz" uniqKey="Grdzelishvili V">VZ Grdzelishvili</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cinatl, J" uniqKey="Cinatl J">J Cinatl</name></author><author><name sortKey="Morgenstern, B" uniqKey="Morgenstern B">B Morgenstern</name></author><author><name sortKey="Bauer, G" uniqKey="Bauer G">G Bauer</name></author><author><name sortKey="Chandra, P" uniqKey="Chandra P">P Chandra</name></author><author><name sortKey="Rabenau, H" uniqKey="Rabenau H">H Rabenau</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Moreno, H" uniqKey="Moreno H">H Moreno</name></author><author><name sortKey="Tejero, H" uniqKey="Tejero H">H Tejero</name></author><author><name sortKey="De La Torre, Jc" uniqKey="De La Torre J">JC de la Torre</name></author><author><name sortKey="Domingo, E" uniqKey="Domingo E">E Domingo</name></author><author><name sortKey="Martin, V" uniqKey="Martin V">V Martin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Agudo, R" uniqKey="Agudo R">R Agudo</name></author><author><name sortKey="Arias, A" uniqKey="Arias A">A Arias</name></author><author><name sortKey="Pariente, N" uniqKey="Pariente N">N Pariente</name></author><author><name sortKey="Perales, C" uniqKey="Perales C">C Perales</name></author><author><name sortKey="Escarmis, C" uniqKey="Escarmis C">C Escarmis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De La Torre, Jc" uniqKey="De La Torre J">JC de la Torre</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Agudo, R" uniqKey="Agudo R">R Agudo</name></author><author><name sortKey="Arias, A" uniqKey="Arias A">A Arias</name></author><author><name sortKey="Domingo, E" uniqKey="Domingo E">E Domingo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Arnold, Jj" uniqKey="Arnold J">JJ Arnold</name></author><author><name sortKey="Vignuzzi, M" uniqKey="Vignuzzi M">M Vignuzzi</name></author><author><name sortKey="Stone, Jk" uniqKey="Stone J">JK Stone</name></author><author><name sortKey="Andino, R" uniqKey="Andino R">R Andino</name></author><author><name sortKey="Cameron, Ce" uniqKey="Cameron C">CE Cameron</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gong, P" uniqKey="Gong P">P Gong</name></author><author><name sortKey="Peersen, Ob" uniqKey="Peersen O">OB Peersen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Thompson, Aa" uniqKey="Thompson A">AA Thompson</name></author><author><name sortKey="Albertini, Ra" uniqKey="Albertini R">RA Albertini</name></author><author><name sortKey="Peersen, Ob" uniqKey="Peersen O">OB Peersen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Prindle, Mj" uniqKey="Prindle M">MJ Prindle</name></author><author><name sortKey="Schmitt, Mw" uniqKey="Schmitt M">MW Schmitt</name></author><author><name sortKey="Parmeggiani, F" uniqKey="Parmeggiani F">F Parmeggiani</name></author><author><name sortKey="Loeb, La" uniqKey="Loeb L">LA Loeb</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Graci, Jd" uniqKey="Graci J">JD Graci</name></author><author><name sortKey="Gnadig, Nf" uniqKey="Gnadig N">NF Gnadig</name></author><author><name sortKey="Galarraga, Je" uniqKey="Galarraga J">JE Galarraga</name></author><author><name sortKey="Castro, C" uniqKey="Castro C">C Castro</name></author><author><name sortKey="Vignuzzi, M" uniqKey="Vignuzzi M">M Vignuzzi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vignuzzi, M" uniqKey="Vignuzzi M">M Vignuzzi</name></author><author><name sortKey="Stone, Jk" uniqKey="Stone J">JK Stone</name></author><author><name sortKey="Arnold, Jj" uniqKey="Arnold J">JJ Arnold</name></author><author><name sortKey="Cameron, Ce" uniqKey="Cameron C">CE Cameron</name></author><author><name sortKey="Andino, R" uniqKey="Andino R">R Andino</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Denison, Mr" uniqKey="Denison M">MR Denison</name></author><author><name sortKey="Graham, Rl" uniqKey="Graham R">RL Graham</name></author><author><name sortKey="Donaldson, Ef" uniqKey="Donaldson E">EF Donaldson</name></author><author><name sortKey="Eckerle, Ld" uniqKey="Eckerle L">LD Eckerle</name></author><author><name sortKey="Baric, Rs" uniqKey="Baric R">RS Baric</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mi, S" uniqKey="Mi S">S Mi</name></author><author><name sortKey="Durbin, R" uniqKey="Durbin R">R Durbin</name></author><author><name sortKey="Huang, Hv" uniqKey="Huang H">HV Huang</name></author><author><name sortKey="Rice, Cm" uniqKey="Rice C">CM Rice</name></author><author><name sortKey="Stollar, V" uniqKey="Stollar V">V Stollar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Scheidel, Lm" uniqKey="Scheidel L">LM Scheidel</name></author><author><name sortKey="Stollar, V" uniqKey="Stollar V">V Stollar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Manns, Mp" uniqKey="Manns M">MP Manns</name></author><author><name sortKey="Foster, Gr" uniqKey="Foster G">GR Foster</name></author><author><name sortKey="Rockstroh, Jk" uniqKey="Rockstroh J">JK Rockstroh</name></author><author><name sortKey="Zeuzem, S" uniqKey="Zeuzem S">S Zeuzem</name></author><author><name sortKey="Zoulim, F" uniqKey="Zoulim F">F Zoulim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cummings, Kj" uniqKey="Cummings K">KJ Cummings</name></author><author><name sortKey="Lee, Sm" uniqKey="Lee S">SM Lee</name></author><author><name sortKey="West, Es" uniqKey="West E">ES West</name></author><author><name sortKey="Cid Ruzafa, J" uniqKey="Cid Ruzafa J">J Cid-Ruzafa</name></author><author><name sortKey="Fein, Sg" uniqKey="Fein S">SG Fein</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Davis, Gl" uniqKey="Davis G">GL Davis</name></author><author><name sortKey="Esteban Mur, R" uniqKey="Esteban Mur R">R Esteban-Mur</name></author><author><name sortKey="Rustgi, V" uniqKey="Rustgi V">V Rustgi</name></author><author><name sortKey="Hoefs, J" uniqKey="Hoefs J">J Hoefs</name></author><author><name sortKey="Gordon, Sc" uniqKey="Gordon S">SC Gordon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mccormick, Jb" uniqKey="Mccormick J">JB McCormick</name></author><author><name sortKey="King, Ij" uniqKey="King I">IJ King</name></author><author><name sortKey="Webb, Pa" uniqKey="Webb P">PA Webb</name></author><author><name sortKey="Scribner, Cl" uniqKey="Scribner C">CL Scribner</name></author><author><name sortKey="Craven, Rb" uniqKey="Craven R">RB Craven</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hall, Cb" uniqKey="Hall C">CB Hall</name></author><author><name sortKey="Walsh, Ee" uniqKey="Walsh E">EE Walsh</name></author><author><name sortKey="Hruska, Jf" uniqKey="Hruska J">JF Hruska</name></author><author><name sortKey="Betts, Rf" uniqKey="Betts R">RF Betts</name></author><author><name sortKey="Hall, Wj" uniqKey="Hall W">WJ Hall</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wyde, Pr" uniqKey="Wyde P">PR Wyde</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bouvet, M" uniqKey="Bouvet M">M Bouvet</name></author><author><name sortKey="Debarnot, C" uniqKey="Debarnot C">C Debarnot</name></author><author><name sortKey="Imbert, I" uniqKey="Imbert I">I Imbert</name></author><author><name sortKey="Selisko, B" uniqKey="Selisko B">B Selisko</name></author><author><name sortKey="Snijder, Ej" uniqKey="Snijder E">EJ Snijder</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, Y" uniqKey="Chen Y">Y Chen</name></author><author><name sortKey="Cai, H" uniqKey="Cai H">H Cai</name></author><author><name sortKey="Pan, J" uniqKey="Pan J">J Pan</name></author><author><name sortKey="Xiang, N" uniqKey="Xiang N">N Xiang</name></author><author><name sortKey="Tien, P" uniqKey="Tien P">P Tien</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, Y" uniqKey="Chen Y">Y Chen</name></author><author><name sortKey="Tao, J" uniqKey="Tao J">J Tao</name></author><author><name sortKey="Sun, Y" uniqKey="Sun Y">Y Sun</name></author><author><name sortKey="Wu, A" uniqKey="Wu A">A Wu</name></author><author><name sortKey="Su, C" uniqKey="Su C">C Su</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fortune, Jm" uniqKey="Fortune J">JM Fortune</name></author><author><name sortKey="Pavlov, Yi" uniqKey="Pavlov Y">YI Pavlov</name></author><author><name sortKey="Welch, Cm" uniqKey="Welch C">CM Welch</name></author><author><name sortKey="Johansson, E" uniqKey="Johansson E">E Johansson</name></author><author><name sortKey="Burgers, Pm" uniqKey="Burgers P">PM Burgers</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Karthikeyan, R" uniqKey="Karthikeyan R">R Karthikeyan</name></author><author><name sortKey="Vonarx, Ej" uniqKey="Vonarx E">EJ Vonarx</name></author><author><name sortKey="Straffon, Af" uniqKey="Straffon A">AF Straffon</name></author><author><name sortKey="Simon, M" uniqKey="Simon M">M Simon</name></author><author><name sortKey="Faye, G" uniqKey="Faye G">G Faye</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Reha Krantz, Lj" uniqKey="Reha Krantz L">LJ Reha-Krantz</name></author><author><name sortKey="Stocki, S" uniqKey="Stocki S">S Stocki</name></author><author><name sortKey="Nonay, Rl" uniqKey="Nonay R">RL Nonay</name></author><author><name sortKey="Dimayuga, E" uniqKey="Dimayuga E">E Dimayuga</name></author><author><name sortKey="Goodrich, Ld" uniqKey="Goodrich L">LD Goodrich</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Morrison, A" uniqKey="Morrison A">A Morrison</name></author><author><name sortKey="Sugino, A" uniqKey="Sugino A">A Sugino</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shcherbakova, Pv" uniqKey="Shcherbakova P">PV Shcherbakova</name></author><author><name sortKey="Pavlov, Yi" uniqKey="Pavlov Y">YI Pavlov</name></author><author><name sortKey="Chilkova, O" uniqKey="Chilkova O">O Chilkova</name></author><author><name sortKey="Rogozin, Ib" uniqKey="Rogozin I">IB Rogozin</name></author><author><name sortKey="Johansson, E" uniqKey="Johansson E">E Johansson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Perales, C" uniqKey="Perales C">C Perales</name></author><author><name sortKey="Martin, V" uniqKey="Martin V">V Martin</name></author><author><name sortKey="Domingo, E" uniqKey="Domingo E">E Domingo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sidwell, Rw" uniqKey="Sidwell R">RW Sidwell</name></author><author><name sortKey="Huffman, Jh" uniqKey="Huffman J">JH Huffman</name></author><author><name sortKey="Khare, Gp" uniqKey="Khare G">GP Khare</name></author><author><name sortKey="Allen, Lb" uniqKey="Allen L">LB Allen</name></author><author><name sortKey="Witkowski, Jt" uniqKey="Witkowski J">JT Witkowski</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Furuta, Y" uniqKey="Furuta Y">Y Furuta</name></author><author><name sortKey="Takahashi, K" uniqKey="Takahashi K">K Takahashi</name></author><author><name sortKey="Fukuda, Y" uniqKey="Fukuda Y">Y Fukuda</name></author><author><name sortKey="Kuno, M" uniqKey="Kuno M">M Kuno</name></author><author><name sortKey="Kamiyama, T" uniqKey="Kamiyama T">T Kamiyama</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Baranovich, T" uniqKey="Baranovich T">T Baranovich</name></author><author><name sortKey="Wong, Ss" uniqKey="Wong S">SS Wong</name></author><author><name sortKey="Armstrong, J" uniqKey="Armstrong J">J Armstrong</name></author><author><name sortKey="Marjuki, H" uniqKey="Marjuki H">H Marjuki</name></author><author><name sortKey="Webby, Rj" uniqKey="Webby R">RJ Webby</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pfeiffer, Jk" uniqKey="Pfeiffer J">JK Pfeiffer</name></author><author><name sortKey="Kirkegaard, K" uniqKey="Kirkegaard K">K Kirkegaard</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>France</li><li>États-Unis</li></country><region><li>Tennessee</li><li>Île-de-France</li></region><settlement><li>Paris</li></settlement></list><tree><country name="États-Unis"><region name="Tennessee"><name sortKey="Smith, Everett Clinton" sort="Smith, Everett Clinton" uniqKey="Smith E" first="Everett Clinton" last="Smith">Everett Clinton Smith</name></region><name sortKey="Denison, Mark R" sort="Denison, Mark R" uniqKey="Denison M" first="Mark R." last="Denison">Mark R. Denison</name><name sortKey="Denison, Mark R" sort="Denison, Mark R" uniqKey="Denison M" first="Mark R." last="Denison">Mark R. Denison</name><name sortKey="Denison, Mark R" sort="Denison, Mark R" uniqKey="Denison M" first="Mark R." last="Denison">Mark R. Denison</name><name sortKey="Smith, Everett Clinton" sort="Smith, Everett Clinton" uniqKey="Smith E" first="Everett Clinton" last="Smith">Everett Clinton Smith</name></country><country name="France"><region name="Île-de-France"><name sortKey="Blanc, Herve" sort="Blanc, Herve" uniqKey="Blanc H" first="Hervé" last="Blanc">Hervé Blanc</name></region><name sortKey="Vignuzzi, Marco" sort="Vignuzzi, Marco" uniqKey="Vignuzzi M" first="Marco" last="Vignuzzi">Marco Vignuzzi</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/SrasV1/Data/France/Analysis
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000161 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/France/Analysis/biblio.hfd -nk 000161 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= SrasV1
|flux= France
|étape= Analysis
|type= RBID
|clé= PMC:3744431
|texte= Coronaviruses Lacking Exoribonuclease Activity Are Susceptible to Lethal Mutagenesis: Evidence for Proofreading and Potential Therapeutics
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/France/Analysis/RBID.i -Sk "pubmed:23966862" \
| HfdSelect -Kh $EXPLOR_AREA/Data/France/Analysis/biblio.hfd \
| NlmPubMed2Wicri -a SrasV1
| This area was generated with Dilib version V0.6.33. |  |