A research team led by Rice University’s Yang Gao has uncovered new insights into the molecular mechanisms of ADAR1, a protein that regulates ribonucleic acid (RNA) induced immune responses. Their findings, published in Molecular Cell March 17, could open new pathways for treating autoimmune diseases and enhancing cancer immunotherapy.

A research team led by Rice's Yang Gao has uncovered new insights into the molecular mechanisms of ADAR1. Photo by Jeff Fitlow/Rice University.
ADAR1 converts adenosine to inosine in double-stranded RNA, a process essential for preventing unwarranted immune responses, yet the molecular basis of this editing had remained unclear. Through detailed biochemical profiling and structural analysis, researchers found that ADAR1’s editing activity depends on RNA sequence, duplex length and mismatches near the editing site. High-resolution structures of ADAR1 bound to RNA reveal its mechanisms for RNA binding, substrate selection and dimerization.

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. These insights pave the way for novel therapeutic strategies targeting ADAR1-related diseases.

ADAR1’s RNA editing mechanism

Researchers used biochemical and RNA sequencing analyses to explore how disease-associated mutations affect ADAR1’s function, demonstrating that specific mutations impair the editing of shorter RNA duplexes. The results could potentially contribute to defects observed in autoimmune disorders. This research underscores the essential role of RNA-binding domain 3, a key portion of ADAR1, in maintaining the protein’s activity and stability.

Moreover, the scientist’s high-resolution structural models revealed previously unknown interactions between ADAR1 and RNA. These findings provide a framework for understanding how ADAR1 mutations contribute to disease and how editing activity can be modulated for therapeutic benefit.

The researchers said they hope to develop targeted treatments that enhance or inhibit ADAR1 activity, depending on the disease context, by leveraging these insights. This could be valuable in cancer immunotherapy, where manipulating ADAR1 levels may improve the immune system’s ability to recognize and attack tumors.

RNA-based therapeutics

Understanding the structural and biochemical properties of ADAR1 could also aid in designing drugs that fine-tune RNA editing for specific therapeutic goals with potential applications in gene therapy and precision medicine.

Additionally, the study’s findings may broadly influence 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, a postdoctoral fellow in Gao’s lab and first author of this study.

Source: https://news.rice.edu/news/2025/scientists-gain-insight-rna-editing-protein-could-lead-improved-treatment-cancer