Improving adenine and dual base editors through introduction of TadA-8e and Rad51DBD

Niannian Xue, Xu Liu, Dan Zhang, Youming Wu, Yi Zhong, Jinxin Wang, Wenjing Fan, Haixia Jiang, Biyun Zhu, Xiyu Ge, Rachel V. L. Gonzalez, Liang Chen, Shun Zhang, Peilu She, Zhilin Zhong, Jianjian Sun, Xi Chen, Liren Wang, Zhimin Gu, Ping Zhu, Mingyao Liu, Dali Li (), Tao P. Zhong () and Xiaohui Zhang ()
Additional contact information
Niannian Xue: East China Normal University
Xu Liu: East China Normal University
Dan Zhang: East China Normal University
Youming Wu: Chinese Academy of Medical Sciences & Peking Union Medical College
Yi Zhong: East China Normal University
Jinxin Wang: Chinese Academy of Medical Sciences & Peking Union Medical College
Wenjing Fan: Chinese Academy of Medical Sciences & Peking Union Medical College
Haixia Jiang: Shanghai Jiao Tong University
Biyun Zhu: East China Normal University
Xiyu Ge: University of Illinois at Urbana-Champaign
Rachel V. L. Gonzalez: Columbia University
Liang Chen: East China Normal University
Shun Zhang: East China Normal University
Peilu She: East China Normal University
Zhilin Zhong: East China Normal University
Jianjian Sun: East China Normal University
Xi Chen: BRL Medicine, Inc.
Liren Wang: East China Normal University
Zhimin Gu: Chinese Academy of Medical Sciences & Peking Union Medical College
Ping Zhu: Guangdong Academy of Medical Sciences
Mingyao Liu: East China Normal University
Dali Li: East China Normal University
Tao P. Zhong: East China Normal University
Xiaohui Zhang: East China Normal University

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Base editors, including dual base editors, are innovative techniques for efficient base conversions in genomic DNA. However, the low efficiency of A-to-G base conversion at positions proximal to the protospacer adjacent motif (PAM) and the A/C simultaneous conversion of the dual base editor hinder their broad applications. In this study, through fusion of ABE8e with Rad51 DNA-binding domain, we generate a hyperactive ABE (hyABE) which offers improved A-to-G editing efficiency at the region (A10-A15) proximal to the PAM, with 1.2- to 7-fold improvement compared to ABE8e. Similarly, we develop optimized dual base editors (eA&C-BEmax and hyA&C-BEmax) with markedly improved simultaneous A/C conversion efficiency (1.2-fold and 1.5-fold improvement, respectively) compared to A&C-BEmax in human cells. Moreover, these optimized base editors catalyze efficiently nucleotide conversions in zebrafish embryos to mirror human syndrome or in human cells to potentially treat genetic diseases, indicating their great potential in broad applications for disease modeling and gene therapy.

Date: 2023
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DOI: 10.1038/s41467-023-36887-1

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