RNA genome conservation and secondary structure in SARS-CoV-2 and SARS-related viruses

Ramya Rangan; Ivan N. Zheludev; Rhiju Das

The frameshifting element (FSE) is located in ORF1ab and is involved in regulating a (-1) ribosomal frameshift event that is necessary for producing ORF1b. The FSE consists of a conserved pseudoknot structure that regulates the rate of ribosomal frameshifting at an upstream slippery site. 7 This domain is nearly exactly conserved between SARS-CoV and SARS-CoV-2, suggesting a similar mechanism for ribosomal pausing and slippage between the two viruses. 25 The 3´ UTR contains various domains critical for regulating viral RNA synthesis and potentially translation. The most 5´ region of the 3´ UTR includes a switch-like domain involving mutually exclusive formation of a pseudoknot and stem-loop, both of which are essential for viral replication with putative roles in establishing the kinetics of RNA synthesis. 6, 26 The hyper-variable region (HVR) is not essential for viral RNA synthesis, as this can be removed while allowing for viral replication in tissue culture; however, viruses without this domain have lower pathogenicity in mice. 27 This domain contains a completely conserved octonucleotide sequence with unconfirmed functional significance. The stem-loop II-like motif (s2m) is another subregion of the HVR that is conserved in SARS-CoV-2 and other coronaviruses. A crystal structure of the SARS s2m domain has been shown to be homologous to an rRNA loop that binds translation initiation proteins, leading this domain to have a proposed role in recruiting host translational machinery. 28 The domain has been proposed to be a selfish element due to its recurrence in numerous virus families outside the Coronaviridae, but its function is not well understood. 29