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 () and Zhihu Zhao ()
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Yan Zhang: Beijing institute of Biotechnology
Kun Huang: Huazhong Agricultural University
Dejian Xie: Wuhan Frasergen Bioinformatics Co., Ltd
Jian You Lau: University of Edinburgh
Wenlong Shen: Beijing institute of Biotechnology
Ping Li: Beijing institute of Biotechnology
Dong Wang: University of Hong Kong, Queen Mary Hospital
Zhong Zou: Huazhong Agricultural University
Shu Shi: Beijing institute of Biotechnology
Hongguang Ren: Beijing institute of Biotechnology
Youliang Wang: Beijing institute of Biotechnology
Youzhi Mao: Wuhan Frasergen Bioinformatics Co., Ltd
Meilin Jin: Huazhong Agricultural University
Grzegorz Kudla: University of Edinburgh
Zhihu Zhao: Beijing institute of Biotechnology

Nature Communications, 2021, vol. 12, issue 1, 1-12

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-25999-1

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