Authors
Asif Rakib, Arnab Das, Subhas C Bera, Jelmer Cnossen, Refugio Robles-Sikisaka, Meghan V Diefenbacher, Pim P B America, Misha Klein, Thomas K Anderson, John C Marecki, Bing Wang, Eline Bogers, Joy Y Feng, John P Bilello, Flávia S Papini, Quinte Smitskamp, Timothy P Sheahan, Jamie J Arnold, Andrew Routh, Irina Artsimovitch, Robert N Kirchdoerfer, Craig E Cameron, Kevin D Raney, David Dulin
Published in
Science advances. Volume 12. Issue 25. Pages eadz9231. Jun 19, 2026. Epub Jun 19, 2026.
Abstract
Polymerase template switching is an essential mechanism in coronaviruses (CoVs) enabling both subgenomic RNA synthesis and increasing genomic diversity via recombination. Despite its importance, the CoV polymerase template-switching molecular mechanism remains unclear. Using magnetic tweezers, we show that the CoV nonstructural protein (nsp) 13-helicase drives intramolecular polymerase template switching, followed by copy-back RNA synthesis. This activity requires nsp13-helicase adenosine triphosphatase activity and a duplex RNA downstream of the CoV polymerase. Remdesivir and molnupiravir are antiviral nucleotide analogs reported to stall the viral polymerase and induce mutations in genome, respectively. Unexpectedly, we show that their incorporation in the nascent strand increases copy-back RNA synthesis in vitro and decreases recombination events in infected cells. We propose a mechanism of action where these analogs' incorporation traps replication complex in a recombination intermediate, preventing viral RNA utilization. Our study highlights the importance of investigating nucleotide analog mechanisms in replication complexes beyond the polymerase.
PMID:
42319933
Bibliographic data and abstract were imported from PubMed on 20 Jun 2026.
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