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
Affiliations
Yan Zhao
Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, China; Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, China; Department of Computational Molecular Biology, Max-Planck-Institute for Molecular Genetics, Berlin 14195, Germany; Department of Mathematics and Computer Science, Free University Berlin, Berlin 14195, Germany
Jing Sun
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
Yunfei Li
Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, China; Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, China
Zhengxuan Li
Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, China; Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, China
Yu Xie
Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, China; Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, China
Ruoqing Feng
Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, China; Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, China
Jincun Zhao
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; Corresponding author
Yuhui Hu
Shenzhen Key Laboratory of Gene Regulation and Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, China; Department of Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen 518005, China; Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China; Corresponding author
Summary: 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.
