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Transcription-wide impact by RESCUE-induced off-target single-nucleotide variants in mammalian cells 
Guo Li1,2,3,† , Xiaoning Zhu3,† , Yihan Wang4,† , Hongru Ma1,2 , Yuzhe Wang3 , Hanyu Wu3 , Xiangyang Li5 , Yiling Wang2 , Jianen Gao4 , Xuexin Chen6 , Xingxu Huang7 , Yuan Yao1,2,* , Xiaoxiang Hu3,*
1College of Chemical and Biological Engineering, Zhejiang University, Hangzhou 310027, China
2ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou 311200, China
3State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China
4National Research Institute for Family Planning, Beijing 100081, China
5School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
6Institute of Insect Sciences, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou 310058, China
7Zhejiang Lab, Hangzhou 311121, China
†These authors contributed equally to this work
*Correspondence to:Yuan Yao , Email:yyao1@zju.edu.cn Xiaoxiang Hu , Email:huxx@cau.edu.cn
J Mol Cell Biol, Volume 15, Issue 2, February 2023, mjad011,  https://doi.org/10.1093/jmcb/mjad011
Keyword: transcription-wide, off-target, SNV, RESCUE, RNA

RNA base editing is a promising tool in precise molecular therapy. Currently, there are two widely used RNA base editors, REPAIR and RESCUE. REPAIR only facilitates A-to-I conversions, while RESCUE performs both A-to-I and C-to-U conversions. Thus, RESCUE can generate twice the number of mutations compared to REPAIR. However, transcription-wide impact due to RESCUE-induced off-target single-nucleotide variants (SNVs) is not fully appreciated. Therefore, to determine the off-target effects of RESCUE-mediated editing, we employed transcription-wide sequencing on cells edited by RESCUE. The SNVs showed different off-target effects on mRNA, circRNA, lncRNA, and miRNA expression patterns and their interacting networks. Our results illustrate the transcription-wide impact of RESCUE-induced off-target SNVs and highlight the need for careful characterization of the off-target impact by this editing platform.


Volume 15, Issue 2
February 2023