Abstract
SummaryThe Coronaviridae is a family of positive-strand RNA viruses that includes SARS-CoV-2, the etiologic agent of the COVID-19 pandemic. Bearing the largest single-stranded RNA genomes in nature, coronaviruses are critically dependent on long-distance RNA-RNA interactions to regulate the viral transcription and replication pathways. Here we experimentally mapped the in vivo RNA-RNA interactome of the full-length SARS-CoV-2 genome and subgenomic mRNAs. We uncovered a network of RNA-RNA interactions spanning tens of thousands of nucleotides. These interactions reveal that the viral genome and subgenomes adopt alternative topologies inside cells and engage in different interactions with host RNAs. Notably, we discovered a long-range RNA-RNA interaction, the FSE-arch, that encircles the programmed ribosomal frameshifting element. The FSE-arch is conserved in the related MERS-CoV and is under purifying selection. Our findings illuminate RNA structure-based mechanisms governing replication, discontinuous transcription, and translation of coronaviruses and will aid future efforts to develop antiviral strategies.
Highlights
RNA viruses are the dominant component of the eukaryotic virome (Dolja and Koonin, 2018)
The SARS-CoV-2 Genome and subgenomic mRNAs (sgmRNAs) Adopt Alternative Co-existing Topologies that Involve LongDistance Base-Pairing Inside the host, the genomic RNA (gRNA) of SARS-CoV-2 is transcribed into sgmRNA (Figure 2A)
We selectively pulled down the full-length positive sense SARSCoV-2 genome from in vivo crosslinked, SARS-CoV-2-inoculated Vero E6/TMPRSS2 cells (Matsuyama et al, 2020), using a tiling array of antisense probes for ORF1a/b, which resulted in a highly enriched gRNA fraction (Figure 2C)
Summary
Highlights d Comprehensive RNA-RNA networks of the SARS-CoV-2 genome and subgenomes inside cells. Coronaviruses use RNA structure to regulate their function. Ziv et al identified maps of RNA-RNA interactions along the SARS-CoV-2 genome and subgenomes inside cells, revealing long-range basepairing between distal elements, alternative co-existing RNA topologies, and interactions between virus and host RNA and providing insights into the coronavirus modes of action. D Long-range structures spanning thousands of bases resulting in dynamic topologies d Multiple site-specific interactions between host and virus RNAs d An arch around the ribosomal frameshifting element is under purifying selection. December 17, 2020 a 2020 The Authors.
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