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

• DOI: 10.1016/j.molcel.2020.11.004
• Publication Date: 2020-11-05T17:13:11Z
• Authors: Omer Ziv; Jonathan Price; Lyudmila Shalamova; Tsveta Kamenova; Ian Goodfellow; Friedemann Weber; Eric A. Miska
• Keywords: 0301 basic medicine; Transcription, Genetic; coronavirus; Genome, Viral; Virus Replication; Article; discontinuous transcription; 03 medical and health sciences; host-virus; ribosomal frameshifting; Chlorocebus aethiops; COMRADES; Animals; Humans; RNA structure; Molecular Biology; Vero Cells; 0303 health sciences; SARS-CoV-2; COVID-19; Frameshifting, Ribosomal; Cell Biology; RNA-RNA interaction; 3. Good health; Protein Biosynthesis; RNA, Viral; FSE-arch

SUMMARYTheCoronaviridaeis 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 thein vivoRNA-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.