A rationally engineered cytosine base editor retains high on-target activity while reducing both DNA and RNA off-target effects.,Nature Methods

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A rationally engineered cytosine base editor retains high on-target activity while reducing both DNA and RNA off-target effects.
Nature Methods ( IF 36.1 ) Pub Date : 2020-05-18 , DOI: 10.1038/s41592-020-0832-x
Erwei Zuo _{1,

2} , Yidi Sun _{3,

4} , Tanglong Yuan ₁ , Bingbing He ₂ , Changyang Zhou ₂ , Wenqin Ying ₂ , Jing Liu ₁ , Wu Wei _{4,

5} , Rong Zeng _{3,

6} , Yixue Li _{4,

6,

7,

8} , Hui Yang _{2,

9}

Affiliation

Shenzhen Branch, Guangdong Laboratory for Lingnan Modern Agriculture, Genome Analysis Laboratory of the Ministry of Agriculture, Agricultural Genomics Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen, China.
Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
CAS Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
Bio-Med Big Data Center, Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
Center for Biomedical Informatics, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China.
Department of Life Sciences, Shanghai Tech University, 100 Haike Road, Shanghai, China.
School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
Collaborative Innovation Center for Genetics and Development, Fudan University, Shanghai, China.
Shanghai Center for Bioinformation Technology, Shanghai Academy of Science & Technology, Shanghai, China.

Cytosine base editors (CBEs) offer a powerful tool for correcting point mutations, yet their DNA and RNA off-target activities have caused concerns in biomedical applications. We describe screens of 23 rationally engineered CBE variants, which reveal mutation residues in the predicted DNA-binding site can dramatically decrease the Cas9-independent off-target effects. Furthermore, we obtained a CBE variant-YE1-BE3-FNLS-that retains high on-target editing efficiency while causing extremely low off-target edits and bystander edits.

中文翻译：

合理设计的胞嘧啶碱基编辑器可保持较高的靶向活性，同时降低DNA和RNA的脱靶作用。

胞嘧啶碱基编辑器（CBE）提供了一种功能强大的工具来纠正点突变，但是它们的脱靶DNA和RNA活性引起了生物医学应用的关注。我们描述了23个合理设计的CBE变体的筛选，揭示了预测的DNA结合位点中的突变残基可以显着降低Cas9独立的脱靶效应。此外，我们获得了CBE变体YE1-BE3-FNLS，该变体保留了较高的按目标编辑效率，同时导致极低的离目标编辑和旁观者编辑。

更新日期：2020-05-18

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