AUTHOR=Li Xin , Cheng Zhi , Wang Fang , Chang Jia , Zhao Qiang , Zhou Hao , Liu Chang , Ruan Jishou , Duan Guangyou , Gao Shan 

TITLE=A Negative Feedback Model to Explain Regulation of SARS-CoV-2 Replication and Transcription

JOURNAL=Frontiers in Genetics

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.641445

DOI=10.3389/fgene.2021.641445

ISSN=1664-8021

ABSTRACT=Background: Coronavirus 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.
Results: By 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-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, an 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 nps15 to reach equilibrium between the CoV replication and transcription. 
Conclusions: The 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.