In vivo structure and dynamics of the SARS-CoV-2 RNA genome.
Yan Zhang, Kun Huang, Dejian Xie, Jian You Lau, Wenlong Shen, Ping Li, Dong Wang, Zhong Zou, Shu Shi, Hongguang Ren, Youliang Wang, Youzhi Mao, Meilin Jin, Grzegorz Kudla, Zhihu Zhao
Author Information
Yan Zhang: Beijing institute of Biotechnology, Beijing, China. ORCID
Kun Huang: Unit of Animal Infectious Diseases, National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China.
Jian You Lau: MRC Human Genetics Unit, University of Edinburgh, Edinburgh, EH4 2XU, UK. ORCID
Wenlong Shen: Beijing institute of Biotechnology, Beijing, China.
Ping Li: Beijing institute of Biotechnology, Beijing, China. ORCID
Dong Wang: Department of Microbiology, University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China.
Zhong Zou: Unit of Animal Infectious Diseases, National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China.
Shu Shi: Beijing institute of Biotechnology, Beijing, China.
Hongguang Ren: Beijing institute of Biotechnology, Beijing, China.
Youliang Wang: Beijing institute of Biotechnology, Beijing, China. ORCID
Meilin Jin: Unit of Animal Infectious Diseases, National Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, 430070, China. jinmeilin@mail.hzau.edu.cn.
Grzegorz Kudla: MRC Human Genetics Unit, University of Edinburgh, Edinburgh, EH4 2XU, UK. gkudla@gmail.com. ORCID
Zhihu Zhao: Beijing institute of Biotechnology, Beijing, China. zhaozh@bmi.ac.cn. ORCID
The dynamics of SARS-CoV-2 RNA structure and their functional relevance are largely unknown. Here we develop a simplified SPLASH assay and comprehensively map the in vivo RNA-RNA interactome of SARS-CoV-2 genome across viral life cycle. We report canonical and alternative structures including 5'-UTR and 3'-UTR, frameshifting element (FSE) pseudoknot and genome cyclization in both cells and virions. We provide direct evidence of interactions between Transcription Regulating Sequences, which facilitate discontinuous transcription. In addition, we reveal alternative short and long distance arches around FSE. More importantly, we find that within virions, while SARS-CoV-2 genome RNA undergoes intensive compaction, genome domains remain stable but with strengthened demarcation of local domains and weakened global cyclization. Taken together, our analysis reveals the structural basis for the regulation of replication, discontinuous transcription and translational frameshifting, the alternative conformations and the maintenance of global genome organization during the whole life cycle of SARS-CoV-2, which we anticipate will help develop better antiviral strategies.
References
Annu Rev Virol. 2015 Nov;2(1):265-88
[PMID: 26958916]
