| First Author | Song D | Year | 2026 |
| Journal | Cell | Volume | 189 |
| Issue | 14 | Pages | 4359-4376.e27 |
| PubMed ID | 42269608 | Mgi Jnum | J:387474 |
| Mgi Id | MGI:8352545 | Doi | 10.1016/j.cell.2026.04.047 |
| Citation | Song D, et al. (2026) RNA structure programs endogenous ADAR for precise and efficient editing. Cell |
| abstractText | Leveraging endogenous adenosine deaminase (ADAR) enzymes through engineered ADAR-recruiting RNAs (arRNAs) offers a safe, programmable strategy for RNA editing without exogenous enzyme delivery. Yet an incomplete understanding of ADAR's mechanistic basis has hindered the rational design of arRNAs with improved efficiency and precision. Here, we present LEAPER 3.0 (leveraging endogenous ADAR for programmable editing of RNA), a next-generation RNA-editing platform that integrates AlphaFold 3 structural predictions with systematic biochemical and cellular assays to define the molecular interface between ADAR1 or ADAR2 and double-stranded RNA. These insights enabled the rational optimization of arRNAs to expand the editable sequence range to previously refractory sites, suppress bystander editing within duplex regions, and achieve single-nucleotide discrimination among adjacent adenosines. This work elucidates the structural and mechanistic principles underlying arRNA-mediated editing and establishes a framework for the rational design of highly efficient and precise A-to-I RNA-editing tools. |
