A conserved long-range RNA interaction in SARS-CoV-2 recruits ADAR1 to enhance virus proliferation

Long-range RNA-RNA pairing impacts the genome structure and function of SARS-CoV-2 variants. To understand the structure and function relationships of different SARS-CoV-2 variants that have emerged during the COVID-19 pandemic, we perform high-throughput structure probing and modelling of the genomic structures of the wildtype (WT), Alpha, Beta, Delta and Omicron variants of SARS-CoV-2. We observe that genomes of SARS-CoV-2 variants are generally structurally conserved, and that single-nucleotide variations and interactions with RNA binding proteins can impact RNA structures across the viruses. Importantly, using proximity ligation sequencing, we identify many conserved ultra-long-range RNA-RNA interactions, including one that spans more than 17 kb in both the WT virus and the Omicron variant. We show that mutations that disrupt this 17 kb long-range interaction reduce viral fitness at later stages of its infection cycle, while compensatory mutations partially restore virus fitness. Additionally, we show that this ultra-long-range RNA-RNA interaction structure binds directly to ADAR1 to alter the RNA editing levels on the viral genome. These studies deepen our understanding of RNA structures in the SARS-CoV-2 genome and their ability to interact with host factors to facilitate virus infectivity.

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Publication Details

Journal
Nature Communications
Published
2025-09-26
DOI
https://doi.org/10.1038/s41467-025-63297-2
Citations
1
Primary Topic
RNA regulation and disease
Type
article
Field-Weighted Citation Impact
0.81

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article

A conserved long-range RNA interaction in SARS-CoV-2 recruits ADAR1 to enhance virus proliferation

Yi Hao Wong, Yue Wan, Louis DeFalco, Su Ying Lim et al.
1 citations
Nature Communications
RNA regulation and disease
0.81
article

A conserved long-range RNA interaction in SARS-CoV-2 recruits ADAR1 to enhance virus proliferation

Yi Hao Wong, Yue Wan, Louis DeFalco, Su Ying Lim, Radoslaw M. Sobota, Kiat Yee Tan, Joy S. Xiang, Jian Han, Lin‐Fa Wang, Andres Merits, Siwy Ling Yang, Justin Jang Hann Chu, Roland G. Huber, Chee Keng Mok, Yu Zhang, Zhiya Zhao, Sainan Wang, J. J. Lim
article en
1 citations

Abstract

Long-range RNA-RNA pairing impacts the genome structure and function of SARS-CoV-2 variants. To understand the structure and function relationships of different SARS-CoV-2 variants that have emerged during the COVID-19 pandemic, we perform high-throughput structure probing and modelling of the genomic structures of the wildtype (WT), Alpha, Beta, Delta and Omicron variants of SARS-CoV-2. We observe that genomes of SARS-CoV-2 variants are generally structurally conserved, and that single-nucleotide variations and interactions with RNA binding proteins can impact RNA structures across the viruses. Importantly, using proximity ligation sequencing, we identify many conserved ultra-long-range RNA-RNA interactions, including one that spans more than 17 kb in both the WT virus and the Omicron variant. We show that mutations that disrupt this 17 kb long-range interaction reduce viral fitness at later stages of its infection cycle, while compensatory mutations partially restore virus fitness. Additionally, we show that this ultra-long-range RNA-RNA interaction structure binds directly to ADAR1 to alter the RNA editing levels on the viral genome. These studies deepen our understanding of RNA structures in the SARS-CoV-2 genome and their ability to interact with host factors to facilitate virus infectivity.

Nature CommunicationsVol. 16(1)
University of California, Riverside (US), Agency for Science, Technology and Research (SG), National University of Singapore (SG), Nanyang Technological University (SG), Duke-NUS Medical School (SG), Bioinformatics Institute (SG), University of Tartu (EE), Genome Institute of Singapore (SG), Institute of Molecular and Cell Biology (SG)
National Research Foundation, National Research Foundation Singapore, Eesti Teadusagentuur
Openalex Percentile: Top 23%
RNA regulation and disease
0.81
DOIOpen Access PDFOpenAlex
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