Distinct RNA elements confer specificity to flavivirus RNA cap methylation events

Hongping Dong, Debashish Ray, Suping Ren, Bo Zhang, Francese Puig-Basagoiti, Yuko Takagi, C. Kiong Ho, Hongmin Li, Pei Yong Shi

Research output: Contribution to journalArticle

82 Scopus citations

Abstract

The 5′ end of the flavivirus plus-sense RNA genome contains a type 1 cap (m7GpppAniG), followed by a conserved stem-loop structure. We report that nonstructural protein 5 (NS5) from four serocomplexes of flaviviruses specifically methylates the cap through recognition of the 5′ terminus of viral RNA. Distinct RNA elements are required for the methylations at guanine N-7 on the cap and ribose 2′-OH on the first transcribed nucleotide. In a West Nile virus (WNV) model, N-7 cap methylation requires specific nucleotides at the second and third positions and a 5′ stem-loop structure; in contrast, 2′-OH ribose methylation requires specific nucleotides at the first and second positions, with a minimum 5′ viral RNA of 20 nucleotides. The cap analogues GpppA and m7GpppA are not active substrates for WNV methytransferase. Footprinting experiments using Gppp- and m7Gppp-terminated RNAs suggest that the 5′ termini of RNA substrates interact with NS5 during the sequential methylation reactions. Cap methylations could be inhibited by an antisense oligomer targeting the first 20 nucleotides of WNV genome. The viral RNA-specific cap methylation suggests methyltransferase as a novel target for flavivirus drug discovery.

Original languageEnglish (US)
Pages (from-to)4412-4421
Number of pages10
JournalJournal of virology
Volume81
Issue number9
DOIs
StatePublished - May 2007

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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  • Cite this

    Dong, H., Ray, D., Ren, S., Zhang, B., Puig-Basagoiti, F., Takagi, Y., Ho, C. K., Li, H., & Shi, P. Y. (2007). Distinct RNA elements confer specificity to flavivirus RNA cap methylation events. Journal of virology, 81(9), 4412-4421. https://doi.org/10.1128/JVI.02455-06