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

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

Nature Communications

10.1038/s41467-025-63297-2

https://doi.org/10.1038/s41467-025-63297-2

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, Yue Wan

genomics, SARS-CoV-2, RNA structure, ADAR1

26 September 2025

Yang, S. L., DeFalco, L., Wang, S., Wong, Y. H., Han, J., Mok, C. K., Tan, K. Y., Lim, S. Y., Zhao, Z., Zhang, Y., Lim, J. J. A., Xiang, J. S., Sobota, R., Wang, L.-F., Chu, J. J. H., Merits, A., Huber, R. G., & Wan, Y. (2025). A conserved long-range RNA interaction in SARS-CoV-2 recruits ADAR1 to enhance virus proliferation. Nature Communications, 16(1). https://doi.org/10.1038/s41467-025-63297-2

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.

Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

This research / project is supported by the National Research Foundation - Competitive Research Programme
Grant Reference no. : NRF-CRP27-2021-0003

https://oar.a-star.edu.sg/communities-collections/articles/23404

2041-1723

Genome Institute of Singapore

https://doi.org/10.1038/s41467-025-63297-2