Language
English
Publication Date
4-3-2025
Journal
Molecular Cell
DOI
10.1016/j.molcel.2025.02.017
PMID
40101712
PMCID
PMC11972152
PubMedCentral® Posted Date
4-3-2026
PubMedCentral® Full Text Version
Author MSS
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.
Keywords
Adenosine Deaminase, Humans, RNA Editing, RNA-Binding Proteins, Mutation, RNA, Double-Stranded, Models, Molecular, HEK293 Cells, Binding Sites, Protein Binding, Inosine, Nucleic Acid Conformation, Protein Multimerization
Published Open-Access
yes
Recommended Citation
Deng, Xiangyu; Sun, Lina; Zhang, Min; et al., "Biochemical Profiling and Structural Basis of ADAR1-Mediated RNA Editing" (2025). Faculty, Staff and Students Publications. 6557.
https://digitalcommons.library.tmc.edu/baylor_docs/6557
Graphical Abstract