Abstract
BackgroundCoronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although a preliminary understanding of the replication and transcription of SARS-CoV-2 has recently emerged, their regulation remains unknown.ResultsBy comprehensive analysis of genome sequence and protein structure data, we propose a negative feedback model to explain the regulation of CoV replication and transcription, providing a molecular basis of the “leader-to-body fusion” model. The key step leading to the proposal of our model was that the transcription regulatory sequence (TRS) motifs were identified as the cleavage sites of nsp15, a nidoviral RNA uridylate-specific endoribonuclease (NendoU). According to this model, nsp15 regulates the synthesis of subgenomic RNAs (sgRNAs), and genomic RNAs (gRNAs) by cleaving TRSs. The expression level of nsp15 controls the relative proportions of sgRNAs and gRNAs, which in turn change the expression level of nsp15 to reach equilibrium between the CoV replication and transcription.ConclusionThe replication and transcription of CoVs are regulated by a negative feedback mechanism that influences the persistence of CoVs in hosts. Our findings enrich fundamental knowledge in the field of gene expression and its regulation, and provide new clues for future studies. One important clue is that nsp15 may be an important and ideal target for the development of drugs (e.g., uridine derivatives) against CoVs.
Highlights
Coronavirus disease 2019 (COVID-19) (Shah and Khan, 2020; Tahir et al, 2020) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
The key step leading to the proposal of our model was that the TRS motifs were identified as the cleavage sites of nsp15, mainly due to the integration of information from many aspects, considering: (1) the ratio between sense and antisense reads, and the ratio between contiguous and junction-spanning reads; (2) the identification of canonical and non-canonical TRS motifs; (3) the nsp15 structure in complex with GpU (PDB: 6X1B); (4) the nsp15 ICSs in ORF8; (5) the polyT at the tail of “GTTCGT” or polyA before “ACGAAC,” which ensures the presence of at least one uridine for nsp15 cleavage
In our previous study (Duan et al, 2020), we proposed that the first hairpin has an important role in the functions of the ribosome binding site (RBS) in the 5 UTR of the SARS-CoV-2 genome
Summary
Coronavirus disease 2019 (COVID-19) (Shah and Khan, 2020; Tahir et al, 2020) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 has a genome of ∼30 kb (Jiayuan et al, 2020), including 12 genes that are ORF1a, 1b, spike (S), envelope (E), membrane (M), nucleocapsid (N), ORF3a, 6, 7a, 7b, 8, and 10. The ORF1a and 1b genes encode 16 nonstructural proteins, named from nsp to nsp. The other 10 genes encode four structural proteins (S, E, M, and N) and six accessory proteins (ORF3a, 6, 7a, 7b, 8, and 10) that are yet to be experimentally verified. Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A preliminary understanding of the replication and transcription of SARS-CoV-2 has recently emerged, their regulation remains unknown
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