Pervasive tertiary structure in the dengue virus RNA genome

By Elizabeth A. Dethoff, M. Boerneke, Nandan S. Gokhale, Brejnev Muhire, Darren P. Martin, M. Sacco, M. J. McFadden, Jules B. Weinstein, W. Messer, Stacy M. Horner and 1 more. 2018

105 citations recorded by the source corpus.

Significance RNA viruses usurp and reprogram host cells using short RNA genomes. RNA viruses encode the information required for their replication in both their primary sequences and higher-order structures formed when the RNA genome strand folds back on itself, but the extent of higher-order structure has remained unclear. We use a new high-throughput RNA structure probing technology to identify RNA regions with tertiary folds and discover that roughly one-third of the dengue virus RNA genome forms higher-order interactions, many in regions functionally important for replication. This work suggests that tertiary structure elements might be common in large RNAs, and that these regions might contain pockets targetable by small molecules in the design of antiviral therapeutics. 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.

Subfields: Molecular Biology, Plant Science, Public Health, Environmental and Occupational Health

Citations in the corpus

• Accurate RNA 3D structure prediction using a language model-based deep learning approach (2022, neutral): “For instance, it achieved an F1 score of 0.60 on structured domains in the dengue virus transcriptome (Supplementary Table 19), aligning with results from mutational profiling (RING-MaP) 42,43 .”