The Short- and Long-Range RNA-RNA Interactome of SARS-CoV-2

The 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.
Graphical Abstract
Highlights • Comprehensive RNA-RNA networks of the SARS-CoV-2 genome and subgenomes inside cells • Long-range structures spanning thousands of bases resulting in dynamic topologies • Multiple site-specific interactions between host and virus RNAs • An arch around the ribosomal frameshifting element is under purifying selection
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 base-pairing between distal elements, alternative co-existing RNA topologies, and interactions between virus and host RNA and providing insights into the coronavirus modes of action.