CoV-er all the vases Structural perspectives of SARS-CoV-2 RNA synthesis

The COVID-19 pandemic has claimed millions of lives and devastated the world economy. Garnering insights into the replication cycle of the causative agent, SARS-CoV-2, will aid the development of therapeutics. SARS-CoV-2 possesses one of the largest viral RNA genomes which is approximately 30 kilobases. To successfully replicate this genome, the virus requires the holo-RdRp that is composed of the RNA dependent RNA polymerase (RdRp), nsp12, and its co-factors nsp7 and nsp8. The holo-RdRp associates with several replicative proteins which form the replication-transcription complex (RTC). Herein, we demonstrate the basis for the coupling of the helicase, nsp13, with the holo-RdRp in the nsp132-RTC complex. The structure illuminates the basis for the helicase interaction with the polymerase and led us to propose that the helicase may promote backtracking of the RdRp. Backtracking is a regulatory feature of cellular transcription that describes the reverse motion of the transcriptase on the nucleic acid template. Finally, we present structural results that suggest a mechanism for the nsp132-RTC to turn backtracking on and off; allosterically switching between rapid RNA synthesis and backtracking in response to events at the RdRp active site.