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Cited by 19RNA regulation and diseaseRNA Research and SplicingRNA and protein synthesis mechanisms

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Biochemical profiling and structural basis of ADAR1-mediated RNA editing

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Deng, Xiangyu, Sun, Lina, Zhang, Min, Basavaraj, Rashmi, Wang, Jin, Weng, Yi-Lan, Gao, Yang·2025·Molecular Cell
DOI 10.1016/j.molcel.2025.02.017

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Abstract

ADAR1 regulates RNA-induced immune responses by converting adenosine to inosine in double-stranded RNA. Mutations in ADAR1 are associated with human autoimmune disease, and targeting ADAR1 has been proposed for cancer immunotherapy. However, the molecular mechanisms underlying ADAR1-mediated editing remain unclear. Here, we provide detailed biochemical and structural characterizations of human ADAR1. Our biochemical profiling reveals that ADAR1 editing is both sequence and RNA-duplex-length dependent but can well tolerate mismatches near the editing site. High-resolution ADAR1-RNA complex structures, combined with mutagenesis, elucidate RNA binding, substrate selection, dimerization, and the essential role of RNA-binding domain 3. The ADAR1 structures also help explain the potential defects of disease-associated mutations, where biochemical and RNA sequencing analysis further indicate some of the mutations preferentially impact the editing of RNAs with short duplexes. These findings unveil the molecular basis of ADAR1 editing and provide insights into its immune-regulatory functions and therapeutic potential.

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Metadata

Authors
Deng, X., Sun, L., Zhang, M., Basavaraj, R., Wang, J., Weng, Y.-L., & Gao, Y.
Affiliations
  • Rice University (US)
  • Houston Methodist (US)
  • Baylor College of Medicine (US)
Corresponding author
Gao, Yang
ORCID
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2025-04
Volume
85
Issue
7
Pages
1381-1394.e6
ISSN
1097-2765 (ISSN-L)
DOI
10.1016/j.molcel.2025.02.017
OpenAlex
W4408510466
Cited by
19
References
2
Citations by year
2026: 14 · 2025: 5
FWCI
5.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Cell (acceptedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
Funders
  • Cancer Prevention and Research Institute of Texas (RR190046)
  • National Institute of Environmental Health Sciences (R01ES031511)
  • National Institutes of Health National Cancer Institute (R01CA268518)
  • Rice University
  • Texas A and M University
  • National Institutes of Health (RP220480)
  • Welch Foundation (C-2033-20200401)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
ADAR1, RNA editing, adenosine-to-inosine conversion, double-stranded RNA, mismatch tolerance, RNA binding, protein dimerization, disease-associated mutations, autoimmune disease, cancer immunotherapy
MeSH terms
Adenosine Deaminase, Binding Sites, Humans, Inosine, Models, Molecular, Mutation, Nucleic Acid Conformation, Protein Binding, RNA, Double-Stranded, RNA-Binding Proteins, RNA Editing, Protein Multimerization, HEK293 Cells

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