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- Title
Adenine transversion editors enable precise, efficient A•T-to-C•G base editing in mammalian cells and embryos.
- Authors
Chen, Liang; Hong, Mengjia; Luan, Changming; Gao, Hongyi; Ru, Gaomeng; Guo, Xinyuan; Zhang, Dujuan; Zhang, Shun; Li, Changwei; Wu, Jun; Randolph, Peyton B.; Sousa, Alexander A.; Qu, Chao; Zhu, Yifan; Guan, Yuting; Wang, Liren; Liu, Mingyao; Feng, Bo; Song, Gaojie; Liu, David R.
- Abstract
Base editors have substantial promise in basic research and as therapeutic agents for the correction of pathogenic mutations. The development of adenine transversion editors has posed a particular challenge. Here we report a class of base editors that enable efficient adenine transversion, including precise A•T-to-C•G editing. We found that a fusion of mouse alkyladenine DNA glycosylase (mAAG) with nickase Cas9 and deaminase TadA-8e catalyzed adenosine transversion in specific sequence contexts. Laboratory evolution of mAAG significantly increased A-to-C/T conversion efficiency up to 73% and expanded the targeting scope. Further engineering yielded adenine-to-cytosine base editors (ACBEs), including a high-accuracy ACBE-Q variant, that precisely install A-to-C transversions with minimal Cas9-independent off-targeting effects. ACBEs mediated high-efficiency installation or correction of five pathogenic mutations in mouse embryos and human cell lines. Founder mice showed 44–56% average A-to-C edits and allelic frequencies of up to 100%. Adenosine transversion editors substantially expand the capabilities and possible applications of base editing technology. A base editor for precise adenine transversions is demonstrated in mouse embryos.
- Publication
Nature Biotechnology, 2024, Vol 42, Issue 4, p638
- ISSN
1087-0156
- Publication type
Article
- DOI
10.1038/s41587-023-01821-9