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

Abstract

Highlights d Comprehensive RNA-RNA networks of the SARS-CoV-2 genome and subgenomes inside cells 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

Structure and regulation of coronavirus genomes: state-of-the-art and novel insights from SARS-CoV-2 studies

“…A highly conserved structure element, stemming from the multi-branched loop of the HVR, is the stem-loop II-like motif (s2m). This stem-loop shows extreme sequence and structure similarity to the second stem-loop from the 3 0 UTR of astroviruses and equine rhinovirus [70], and its existence in SARS-CoV-2 is supported under both in vitro and in vivo conditions by multiple studies [33,[35][36][37][38][39]. X-ray crystallography of the s2m revealed that the tertiary folding of the apical pentanucleotide GAGUA loop resembles that of a typical GNRA tetraloop, with the U bulging out of the stack [71].…”

“…A first consensus model of the 5 0 UTR was originally proposed by comparative analysis of nine CoV from the three major CoV groups (alpha, beta, and gamma-CoV), and identified the three major conserved stem-loops SL1, SL2, and SL4 [32]. All three SLs have been consistently predicted and experimentally verified in SARS-CoV-2 [33][34][35][36][37][38][39]. Besides these, up to eight SLs can be present in CoV 5 0 UTRs, with some degree of variation across different genera ( Figure 1).…”

“…The slippery site is boxed in blue. (D) Structure of the FSE-arch enclosing the FSE, as identified by direct RNA-RNA interaction mapping in the SARS-CoV-2 genome, with base-pairs colored according to their relative abundance from Ziv et al [38]. [62,63].…”

“…In addition, the structures of seven stem-loops (8,11,12,13,14,15,16) proposed to enclose the TRS-Bs (boxed in green), with superimposed reactivities from Lan et al [37], are shown. On the bottom, an arc plot shows the long-range interactions identified by direct RNA-RNA interaction mapping in the SARS-CoV-2 genome, colored according to their relative abundance from Ziv et al [38]. The FSE-arch is also indicated.…”

“…Nonetheless, in vivo RNA-RNA interaction capture experiments revealed the existence of several long-range interactions, particularly enriched within ORF1a [38] (Figure 3, bottom). Part of these interactions appears to be mutually-exclusive, suggesting the presence of multiple coexisting alternative conformations.…”