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

Author

Listed:
  • 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
    Suzhou Institute of Systems Medicine)

  • Yi Zhong

    (East China Normal University)

  • Jinxin Wang

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Suzhou Institute of Systems Medicine)

  • Wenjing Fan

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Suzhou Institute of Systems Medicine)

  • 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
    Guangdong Academy of Medical Sciences)

  • Zhilin Zhong

    (East China Normal University)

  • Jianjian Sun

    (East China Normal University
    Guangdong Academy of Medical Sciences)

  • Xi Chen

    (BRL Medicine, Inc.)

  • Liren Wang

    (East China Normal University)

  • Zhimin Gu

    (Chinese Academy of Medical Sciences & Peking Union Medical College
    Suzhou Institute of Systems Medicine)

  • Ping Zhu

    (Guangdong Academy of Medical Sciences)

  • Mingyao Liu

    (East China Normal University
    BRL Medicine, Inc.)

  • Dali Li

    (East China Normal University)

  • Tao P. Zhong

    (East China Normal University)

  • Xiaohui Zhang

    (East China Normal University
    Chinese Academy of Medical Sciences & Peking Union Medical College
    Suzhou Institute of Systems Medicine)

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.

Suggested Citation

  • 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 , 2023. "Improving adenine and dual base editors through introduction of TadA-8e and Rad51DBD," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36887-1
    DOI: 10.1038/s41467-023-36887-1
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    References listed on IDEAS

    as
    1. Alexis C. Komor & Yongjoo B. Kim & Michael S. Packer & John A. Zuris & David R. Liu, 2016. "Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage," Nature, Nature, vol. 533(7603), pages 420-424, May.
    2. Changyang Zhou & Yidi Sun & Rui Yan & Yajing Liu & Erwei Zuo & Chan Gu & Linxiao Han & Yu Wei & Xinde Hu & Rong Zeng & Yixue Li & Haibo Zhou & Fan Guo & Hui Yang, 2019. "Off-target RNA mutation induced by DNA base editing and its elimination by mutagenesis," Nature, Nature, vol. 571(7764), pages 275-278, July.
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