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Proc Natl Acad Sci U S A. 2018 Nov 6;115(45):11513-11518. doi: 10.1073/pnas.1716689115. Epub 2018 Oct 19.

Pervasive tertiary structure in the dengue virus RNA genome.

Author information

1
Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599.
2
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710.
3
Institute of Infectious Disease and Molecular Medicine, University of Cape Town, 7000 Cape Town, South Africa.
4
Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR 97239.
5
Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR 97239 weeks@unc.edu stacy.horner@duke.edu messer@ohsu.edu.
6
Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710; weeks@unc.edu stacy.horner@duke.edu messer@ohsu.edu.
7
Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599; weeks@unc.edu stacy.horner@duke.edu messer@ohsu.edu.

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.

KEYWORDS:

RING-MaP; RNA tertiary structure; genome circularization; viral packaging

PMID:
30341219
PMCID:
PMC6233125
[Available on 2019-05-06]
DOI:
10.1073/pnas.1716689115

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