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

Author:

Liu Yajing,Zhou Changyang,Huang Shisheng,Dang Lu,Wei Yu,He Jun,Zhou Yingsi,Mao Shaoshuai,Tao Wanyu,Zhang Yu,Yang HuiORCID,Huang XingxuORCID,Chi TianORCID

Abstract

AbstractDNA 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.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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