Scientists have made a major discovery about ADAR1—a protein that controls RNA-induced immune responses—paving the way for better treatments for autoimmune diseases and cancer immunotherapy.
ADAR1 converts adenosine to inosine in double-stranded RNA, a key process for preventing unwarranted immune responses, yet the molecular basis of this editing remained unclear.
A research team led by Rice University’s Yang Gao conducted detailed biochemical profiling and structural analysis of ADAR1.
The scientists found that the protein’s editing activity depends on RNA sequence, duplex length, and mismatches near the editing site.
High-resolution structures of ADAR1 bound to RNA reveal how it binds RNA, selects substrates and dimerizes.
“Our study provides a comprehensive understanding of how ADAR1 recognizes and processes RNA,” said Gao, assistant professor of biosciences and a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar, said in a press release.
“These insights pave the way for novel therapeutic strategies targeting ADAR1-related diseases.”
RNA editing mechanism of ADAR1
Using biochemical and RNA sequencing analyses, the researchers explored how disease-associated mutations affect ADAR1’s function, revealing that certain mutations impair the editing of shorter RNA duplexes.
The results could potentially contribute to defects observed in autoimmune disorders.
This research highlights the essential role of RNA-binding domain 3, a key portion of ADAR1, in maintaining the protein’s activity and stability.
Additionally, the high-resolution structural models used by the researchers illustrated previously unknown interactions between ADAR1 and RNA.
These findings establish a foundation for understanding how ADAR1 mutations contribute to disease and how its editing activity can be adjusted for therapeutic benefit.
The researchers said they aim to use the study findings to develop targeted treatments that enhance or inhibit ADAR1 activity, depending on the disease context. This could be crucial for cancer immunotherapy, where adjusting ADAR1 levels may enhance the immune system’s ability to detect and target tumors.
Roadmap for RNA-based therapeutics
Understanding the structural and biochemical properties of ADAR1 could help design drugs that fine-tune RNA editing for specific therapeutic goals—potentially advancing gene therapy and precision medicine.
Moreover, these findings may have broader implications for drug discovery efforts targeting RNA-binding proteins.
“Our structural insights into ADAR1 provide a solid foundation for designing small molecules or engineered proteins that can modulate RNA editing in disease settings,” said Xiangyu Deng, the first author of this study.
Despite its breakthrough, the study has limitations, including its reliance on synthetic RNA substrates that may not fully capture the complexity of natural RNA structures in cells.
“As we continue to explore ADAR1’s function in more complex biological systems, we hope to uncover new therapeutic strategies that leverage its RNA-editing capabilities,” Gao said.
Researchers from the Center for Neuroregeneration at Houston Methodist Research Institute and the Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology at Baylor College of Medicine contributed to the study.
The research was supported by the Welch Foundation, CPRIT, the Rice Startup Fund, and the National Institutes of Health.
The findings of the study were published in Molecular Cell.