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Adenine transversion editors enable precise, efficient A•T-to-C•G base editing in mammalian cells and embryos.
- Source :
- Nature Biotechnology; Apr2024, Vol. 42 Issue 4, p638-650, 13p
- Publication Year :
- 2024
-
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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 10870156
- Volume :
- 42
- Issue :
- 4
- Database :
- Complementary Index
- Journal :
- Nature Biotechnology
- Publication Type :
- Academic Journal
- Accession number :
- 176650928
- Full Text :
- https://doi.org/10.1038/s41587-023-01821-9