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

Siwy Ling Yang (), Louis DeFalco, Sainan Wang, Yi Hao Wong, Jian Han, Chee Keng Mok, Kiat Yee Tan, Su Ying Lim, Zhiya Zhao, Yu Zhang, Jovi Jian An Lim, Joy S. Xiang, Radoslaw Sobota, Lin-Fa Wang, Justin Jang Hann Chu, Andres Merits (), Roland G. Huber () and Yue Wan ()
Additional contact information
Siwy Ling Yang: Technology and Research (A*STAR)
Louis DeFalco: Technology and Research (A*STAR)
Sainan Wang: University of Tartu
Yi Hao Wong: National University of Singapore
Jian Han: Technology and Research (A*STAR)
Chee Keng Mok: Technology and Research (A*STAR)
Kiat Yee Tan: Technology and Research (A*STAR)
Su Ying Lim: Technology and Research (A*STAR)
Zhiya Zhao: Technology and Research (A*STAR)
Yu Zhang: Technology and Research (A*STAR)
Jovi Jian An Lim: Technology and Research (A*STAR)
Joy S. Xiang: Riverside
Radoslaw Sobota: Technology and Research (A*STAR)
Lin-Fa Wang: Duke-NUS Medical School
Justin Jang Hann Chu: National University of Singapore
Andres Merits: University of Tartu
Roland G. Huber: Technology and Research (A*STAR)
Yue Wan: Technology and Research (A*STAR)

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63297-2

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