biostudies-literatureDi MNSFCNational Institutes of HealthNIGMS NIH HHS102190https://www.ebi.ac.uk/biostudies/studies/S-EPMC11077028biostudies-literatureUnknown35(2)RNA base editors should ideally be free of immunogenicity, compact, efficient, and specific, which has not been achieved for C > U editing. Here we first describe a compact C > U editor entirely of human origin, created by fusing the human C > U editing enzyme RESCUE-S to Cas inspired RNA targeting system (CIRTS), a tiny, human-originated programmable RNA-binding domain. This editor, CIRTS-RESCUEv1 (V1), was inefficient. Remarkably, a short histidine-rich domain (HRD), which is derived from the internal disordered region (IDR) in the human CYCT1, a protein capable of liquid-liquid phase separation (LLPS), enhanced V1 editing at on-targets as well as off-targets, the latter effect being minor. The V1-HRD fusion protein formed puncta characteristic of LLPS, and various other IDRs (but not anMolecular therapy. Nucleic acidsExpanding RNA editing toolkit using an IDR-based strategy.PMC11077028R35 GM119840Lv JWu JDi MYan KDickinson BCJing ZYang YChi TGe JRauch SfalseExpanding RNA editing toolkit using an IDR-based strategy.RNA base editors should ideally be free of immunogenicity, compact, efficient, and specific, which has not been achieved for C > U editing. Here we first describe a compact C > U editor entirely of human origin, created by fusing the human C > U editing enzyme RESCUE-S to Cas inspired RNA targeting system (CIRTS), a tiny, human-originated programmable RNA-binding domain. This editor, CIRTS-RESCUEv1 (V1), was inefficient. Remarkably, a short histidine-rich domain (HRD), which is derived from the internal disordered region (IDR) in the human CYCT1, a protein capable of liquid-liquid phase separation (LLPS), enhanced V1 editing at on-targets as well as off-targets, the latter effect being minor. The V1-HRD fusion protein formed puncta characteristic of LLPS, and various other IDRs (but not an2024-01-01T00:00:00Z2024 Jun2026-06-03T04:32:12.9Z2026-04-24T03:09:42.373ZS-EPMC110770283872127910.1016/j.omtn.2024.102190