Pervasive tertiary structure in the dengue virus RNA genome

Elizabeth A. Dethoff, Mark A. Boerneke, Nandan S. Gokhale, Brejnev M. Muhire, Darren P. Martin, Matthew T. Sacco, Michael J. McFadden, Jules B. Weinstein, William Messer, Stacy M. Horner, Kevin M. Weeks

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

RNA virus genomes are efficient and compact carriers of biological information, encoding information required for replication both in their primary sequences and in higher-order RNA structures. However, the ubiquity of RNA elements with higher-order folds-in which helices pack together to form complex 3D structures-and the extent to which these elements affect viral fitness are largely unknown. Here we used single-molecule correlated chemical probing to define secondary and tertiary structures across the RNA genome of dengue virus serotype 2 (DENV2). Higher-order RNA structures are pervasive and involve more than one-third of nucleotides in the DENV2 genomic RNA. These 3D structures promote a compact overall architecture and contribute to viral fitness. Disrupting RNA regions with higher-order structures leads to stable, nonreverting mutants and could guide the development of vaccines based on attenuated RNA viruses. The existence of extensive regions of functional RNA elements with tertiary folds in viral RNAs, and likely many other messenger and noncoding RNAs, means that there are significant regions with pocket-containing surfaces that may serve as novel RNA-directed drug targets.

Original languageEnglish (US)
Pages (from-to)11513-11518
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number45
DOIs
StatePublished - Nov 6 2018

    Fingerprint

Keywords

  • Genome circularization
  • RING-MaP
  • RNA tertiary structure
  • Viral packaging

ASJC Scopus subject areas

  • General

Cite this

Dethoff, E. A., Boerneke, M. A., Gokhale, N. S., Muhire, B. M., Martin, D. P., Sacco, M. T., McFadden, M. J., Weinstein, J. B., Messer, W., Horner, S. M., & Weeks, K. M. (2018). Pervasive tertiary structure in the dengue virus RNA genome. Proceedings of the National Academy of Sciences of the United States of America, 115(45), 11513-11518. https://doi.org/10.1073/pnas.1716689115