Structure-first identification of RNA elements that regulate dengue virus genome architecture and replication

The genomes of RNA viruses encode the information required for replication in host cells both in their linear sequence and in complex higher-order structures. A subset of these RNA genome structures show clear sequence conservation, and have been extensively described for well-characterized viruses....

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2023-04, Vol.120 (15), p.e2217053120-e2217053120
Main Authors: Boerneke, Mark A, Gokhale, Nandan S, Horner, Stacy M, Weeks, Kevin M
Format: Article
Language:English
Subjects:
Amino acid sequence
Antiviral agents
Biological Sciences
Conserved sequence
Dengue
Dengue fever
Fitness
Gene sequencing
Genome, Viral - genetics
Genomes
Humans
Nucleic Acid Conformation
Nucleotide sequence
Protein structure
Proteins
Replication
RNA viruses
RNA Viruses - genetics
RNA, Viral - metabolism
Serotypes
Structural members
Structure-function relationships
Vaccines
Vector-borne diseases
Virus Replication - genetics
Viruses
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Summary:The genomes of RNA viruses encode the information required for replication in host cells both in their linear sequence and in complex higher-order structures. A subset of these RNA genome structures show clear sequence conservation, and have been extensively described for well-characterized viruses. However, the extent to which viral RNA genomes contain functional structural elements-unable to be detected by sequence alone-that nonetheless are critical to viral fitness is largely unknown. Here, we devise a structure-first experimental strategy and use it to identify 22 structure-similar motifs across the coding sequences of the RNA genomes for the four dengue virus serotypes. At least 10 of these motifs modulate viral fitness, revealing a significant unnoticed extent of RNA structure-mediated regulation within viral coding sequences. These viral RNA structures promote a compact global genome architecture, interact with proteins, and regulate the viral replication cycle. These motifs are also thus constrained at the levels of both RNA structure and protein sequence and are potential resistance-refractory targets for antivirals and live-attenuated vaccines. Structure-first identification of conserved RNA structure enables efficient discovery of pervasive RNA-mediated regulation in viral genomes and, likely, other cellular RNAs.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2217053120