A Cas-embedding strategy for minimizing off-target effects of DNA base editors

Yajing Liu, Changyang Zhou, Shisheng Huang, Lu Dang, Yu Wei, Jun He, Yingsi Zhou, Shaoshuai Mao, Wanyu Tao, Yu Zhang, Hui Yang (), Xingxu Huang () and Tian Chi ()
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Yajing Liu: ShanghaiTech University
Changyang Zhou: Chinese Academy of Sciences
Shisheng Huang: ShanghaiTech University
Lu Dang: Cancer Hospital and Institute of Guangzhou Medical University
Yu Wei: Chinese Academy of Sciences
Jun He: ShanghaiTech University
Yingsi Zhou: Chinese Academy of Sciences
Shaoshuai Mao: Chinese Academy of Sciences
Wanyu Tao: ShanghaiTech University
Yu Zhang: ShanghaiTech University
Hui Yang: Chinese Academy of Sciences
Xingxu Huang: ShanghaiTech University
Tian Chi: ShanghaiTech University

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: Abstract DNA base editors, typically comprising editing enzymes fused to the N-terminus of nCas9, display off-target effects on DNA and/or RNA, which have remained an obstacle to their clinical applications. Off-target edits are typically countered via rationally designed point mutations, but the approach is tedious and not always effective. Here, we report that the off-target effects of both A > G and C > T editors can be dramatically reduced without compromising the on-target editing simply by inserting the editing enzymes into the middle of nCas9 at tolerant sites identified using a transposon-based genetic screen. Furthermore, employing this Cas-embedding strategy, we have created a highly specific editor capable of efficient C > T editing at methylated and GC-rich sequences.

Date: 2020
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DOI: 10.1038/s41467-020-19690-0

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