The strand-biased transcription of SARS-CoV-2 and unbalanced inhibition by remdesivir

Yan Zhao; Jing Sun; Yunfei Li; Zhengxuan Li; Yu Xie; Ruoqing Feng; Jincun Zhao; Yuhui Hu

doi:10.1016/j.isci.2021.102857

The strand-biased transcription of SARS-CoV-2 and unbalanced inhibition by remdesivir

iScience. 2021 Aug 20;24(8):102857. doi: 10.1016/j.isci.2021.102857. Epub 2021 Jul 14.

Authors

Yan Zhao^{1

2

3

4}, Jing Sun⁵, Yunfei Li^{1

2}, Zhengxuan Li^{1

2}, Yu Xie^{1

2}, Ruoqing Feng^{1

2}, Jincun Zhao⁵, Yuhui Hu^{1

2

6}

Affiliations

¹ Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, China.
² Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, China.
³ Department of Computational Molecular Biology, Max-Planck-Institute for Molecular Genetics, Berlin 14195, Germany.
⁴ Department of Mathematics and Computer Science, Free University Berlin, Berlin 14195, Germany.
⁵ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510182, Guangdong, China.
⁶ Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China.

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a positive single-stranded RNA virus, causes the coronavirus disease 19 pandemic. During the viral replication and transcription, the RNA-dependent RNA polymerase "jumps" along the genome template, resulting in discontinuous negative-stranded transcripts. Although the sense-mRNA architectures of SARS-CoV-2 were reported, its negative strand was unexplored. Here, we deeply sequenced both strands of RNA and found SARS-CoV-2 transcription is strongly biased to form the sense strand with variable transcription efficiency for different genes. During negative strand synthesis, numerous non-canonical fusion transcripts are also formed, driven by 3-15 nt sequence homology scattered along the genome but more prone to be inhibited by SARS-CoV-2 RNA polymerase inhibitor remdesivir. The drug also represses more of the negative than the positive strand synthesis as supported by a mathematic simulation model and experimental quantifications. Overall, this study opens new sights into SARS-CoV-2 biogenesis and may facilitate the antiviral vaccine development and drug design.

Keywords: mathematical biosciences; systems biology; virology.