Hepatitis C virus NS3 helicase contributes to (−) strand RNA synthesis.

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Název: Hepatitis C virus NS3 helicase contributes to (−) strand RNA synthesis.
Autoři: Ralfs, Philipp, Bressanelli, Stéphane, Günter, Lina M., Gabel, Alexander, Rothhaar, Paul, Price, Kyle J., Tubiana, Thibault, Munschauer, Mathias, Frick, David N., Lohmann, Volker
Zdroj: Nature Communications; 8/27/2025, Vol. 16 Issue 1, p1-21, 21p
Témata: HEPATITIS C, RNA synthesis, GENETIC mutation, HAIRPIN (Genetics), VIRAL replication, RNA replicase, RNA helicase
Abstrakt: Many positive strand RNA viruses encode helicases, but their distinct functions in viral replication cycles is poorly understood. Here, we identify a mutation in the helicase domain of HCV non-structural protein 3 (NS3h), D1467G, which specifically affects (−) strand synthesis, phenocopying mutations in the 3' untranslated region of the genome. D1467G does not impair helicase activity in vitro or the binding of NS3h to critical cis-acting RNA elements, but reduces the interaction of NS3h and NS5B polymerase, potentially contributing to defective (−) strand synthesis. AlphaFold predictions of complexes between NS3h, RNA and/or NS5B suggest that NS3h both remodels the cis-acting RNA elements and unwinds the terminal stem-loop of the HCV genome rendering the template accessible for de novo initiation of (−) strand synthesis by NS5B. Overall, our study provides evidence for a defined function of a viral helicase in (−) strand genome synthesis of a positive strand RNA virus. Specific functions of viral helicases in genome replication of RNA viruses are widely unknown. This study suggests that hepatitis C virus NS3 helicase unwinds stem loop structures at the 3'end of the genome, thereby facilitating (−) strand synthesis. [ABSTRACT FROM AUTHOR]
Copyright of Nature Communications is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Hepatitis C virus NS3 helicase contributes to (−) strand RNA synthesis.
– Name: Author
  Label: Authors
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  Data: <searchLink fieldCode="AR" term="%22Ralfs%2C+Philipp%22">Ralfs, Philipp</searchLink><br /><searchLink fieldCode="AR" term="%22Bressanelli%2C+Stéphane%22">Bressanelli, Stéphane</searchLink><br /><searchLink fieldCode="AR" term="%22Günter%2C+Lina+M%2E%22">Günter, Lina M.</searchLink><br /><searchLink fieldCode="AR" term="%22Gabel%2C+Alexander%22">Gabel, Alexander</searchLink><br /><searchLink fieldCode="AR" term="%22Rothhaar%2C+Paul%22">Rothhaar, Paul</searchLink><br /><searchLink fieldCode="AR" term="%22Price%2C+Kyle+J%2E%22">Price, Kyle J.</searchLink><br /><searchLink fieldCode="AR" term="%22Tubiana%2C+Thibault%22">Tubiana, Thibault</searchLink><br /><searchLink fieldCode="AR" term="%22Munschauer%2C+Mathias%22">Munschauer, Mathias</searchLink><br /><searchLink fieldCode="AR" term="%22Frick%2C+David+N%2E%22">Frick, David N.</searchLink><br /><searchLink fieldCode="AR" term="%22Lohmann%2C+Volker%22">Lohmann, Volker</searchLink>
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  Data: Nature Communications; 8/27/2025, Vol. 16 Issue 1, p1-21, 21p
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  Data: <searchLink fieldCode="DE" term="%22HEPATITIS+C%22">HEPATITIS C</searchLink><br /><searchLink fieldCode="DE" term="%22RNA+synthesis%22">RNA synthesis</searchLink><br /><searchLink fieldCode="DE" term="%22GENETIC+mutation%22">GENETIC mutation</searchLink><br /><searchLink fieldCode="DE" term="%22HAIRPIN+%28Genetics%29%22">HAIRPIN (Genetics)</searchLink><br /><searchLink fieldCode="DE" term="%22VIRAL+replication%22">VIRAL replication</searchLink><br /><searchLink fieldCode="DE" term="%22RNA+replicase%22">RNA replicase</searchLink><br /><searchLink fieldCode="DE" term="%22RNA+helicase%22">RNA helicase</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Many positive strand RNA viruses encode helicases, but their distinct functions in viral replication cycles is poorly understood. Here, we identify a mutation in the helicase domain of HCV non-structural protein 3 (NS3h), D1467G, which specifically affects (−) strand synthesis, phenocopying mutations in the 3' untranslated region of the genome. D1467G does not impair helicase activity in vitro or the binding of NS3h to critical cis-acting RNA elements, but reduces the interaction of NS3h and NS5B polymerase, potentially contributing to defective (−) strand synthesis. AlphaFold predictions of complexes between NS3h, RNA and/or NS5B suggest that NS3h both remodels the cis-acting RNA elements and unwinds the terminal stem-loop of the HCV genome rendering the template accessible for de novo initiation of (−) strand synthesis by NS5B. Overall, our study provides evidence for a defined function of a viral helicase in (−) strand genome synthesis of a positive strand RNA virus. Specific functions of viral helicases in genome replication of RNA viruses are widely unknown. This study suggests that hepatitis C virus NS3 helicase unwinds stem loop structures at the 3'end of the genome, thereby facilitating (−) strand synthesis. [ABSTRACT FROM AUTHOR]
– Name: Abstract
  Label:
  Group: Ab
  Data: <i>Copyright of Nature Communications is the property of Springer Nature and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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