IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-36887-1.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-36887-1
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-36887-1?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Chengdong Zhang & Yuan Yang & Tao Qi & Yuening Zhang & Linghui Hou & Jingjing Wei & Jingcheng Yang & Leming Shi & Sang-Ging Ong & Hongyan Wang & Hui Wang & Bo Yu & Yongming Wang, 2023. "Prediction of base editor off-targets by deep learning," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    2. Qichen Yuan & Xue Gao, 2022. "Multiplex base- and prime-editing with drive-and-process CRISPR arrays," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Guoling Li & Xue Dong & Jiamin Luo & Tanglong Yuan & Tong Li & Guoli Zhao & Hainan Zhang & Jingxing Zhou & Zhenhai Zeng & Shuna Cui & Haoqiang Wang & Yin Wang & Yuyang Yu & Yuan Yuan & Erwei Zuo & Chu, 2024. "Engineering TadA ortholog-derived cytosine base editor without motif preference and adenosine activity limitation," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    4. Shuqian Zhang & Liting Song & Bo Yuan & Cheng Zhang & Jixin Cao & Jinlong Chen & Jiayi Qiu & Yilin Tai & Jingqi Chen & Zilong Qiu & Xing-Ming Zhao & Tian-Lin Cheng, 2023. "TadA reprogramming to generate potent miniature base editors with high precision," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    5. Jianhang Yin & Rusen Lu & Changchang Xin & Yuhong Wang & Xinyu Ling & Dong Li & Weiwei Zhang & Mengzhu Liu & Wutao Xie & Lingyun Kong & Wen Si & Ping Wei & Bingbing Xiao & Hsiang-Ying Lee & Tao Liu & , 2022. "Cas9 exo-endonuclease eliminates chromosomal translocations during genome editing," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    6. Junhao Fu & Qing Li & Xiaoyu Liu & Tianxiang Tu & Xiujuan Lv & Xidi Yin & Jineng Lv & Zongming Song & Jia Qu & Jinwei Zhang & Jinsong Li & Feng Gu, 2021. "Human cell based directed evolution of adenine base editors with improved efficiency," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    7. Jian Wang & Ke Wang & Zhe Deng & Zhiyu Zhong & Guo Sun & Qing Mei & Fuling Zhou & Zixin Deng & Yuhui Sun, 2024. "Engineered cytosine base editor enabling broad-scope and high-fidelity gene editing in Streptomyces," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    8. Jianli Tao & Daniel E. Bauer & Roberto Chiarle, 2023. "Assessing and advancing the safety of CRISPR-Cas tools: from DNA to RNA editing," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    9. Nana Yan & Hu Feng & Yongsen Sun & Ying Xin & Haihang Zhang & Hongjiang Lu & Jitan Zheng & Chenfei He & Zhenrui Zuo & Tanglong Yuan & Nana Li & Long Xie & Wu Wei & Yidi Sun & Erwei Zuo, 2023. "Cytosine base editors induce off-target mutations and adverse phenotypic effects in transgenic mice," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    10. Irina Arnaoutova & Yvonne Aratyn-Schaus & Lisa Zhang & Michael S. Packer & Hung-Dar Chen & Cheol Lee & Sudeep Gautam & Francine M. Gregoire & Dominique Leboeuf & Steven Boule & Thomas P. Fernandez & V, 2024. "Base-editing corrects metabolic abnormalities in a humanized mouse model for glycogen storage disease type-Ia," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    11. Guiquan Zhang & Yao Liu & Shisheng Huang & Shiyuan Qu & Daolin Cheng & Yuan Yao & Quanjiang Ji & Xiaolong Wang & Xingxu Huang & Jianghuai Liu, 2022. "Enhancement of prime editing via xrRNA motif-joined pegRNA," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    12. Ambrocio Sanchez & Pedro Ortega & Ramin Sakhtemani & Lavanya Manjunath & Sunwoo Oh & Elodie Bournique & Alexandrea Becker & Kyumin Kim & Cameron Durfee & Nuri Alpay Temiz & Xiaojiang S. Chen & Reuben , 2024. "Mesoscale DNA features impact APOBEC3A and APOBEC3B deaminase activity and shape tumor mutational landscapes," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    13. Fang Liang & Yu Zhang & Lin Li & Yexin Yang & Ji-Feng Fei & Yanmei Liu & Wei Qin, 2022. "SpG and SpRY variants expand the CRISPR toolbox for genome editing in zebrafish," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    14. Ronghao Chen & Yu Cao & Yajing Liu & Dongdong Zhao & Ju Li & Zhihui Cheng & Changhao Bi & Xueli Zhang, 2023. "Enhancement of a prime editing system via optimal recruitment of the pioneer transcription factor P65," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    15. Feiyu Zhao & Tao Zhang & Xiaodi Sun & Xiyun Zhang & Letong Chen & Hejun Wang & Jinze Li & Peng Fan & Liangxue Lai & Tingting Sui & Zhanjun Li, 2023. "A strategy for Cas13 miniaturization based on the structure and AlphaFold," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    16. Wei Qin & Fang Liang & Sheng-Jia Lin & Cassidy Petree & Kevin Huang & Yu Zhang & Lin Li & Pratishtha Varshney & Philippe Mourrain & Yanmei Liu & Gaurav K. Varshney, 2024. "ABE-ultramax for high-efficiency biallelic adenine base editing in zebrafish," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    17. Yang Xue & Lijun Shang, 2022. "Governance of Heritable Human Gene Editing World-Wide and Beyond," IJERPH, MDPI, vol. 19(11), pages 1-17, May.
    18. Yu Zhang & Yang Liu & Wei Qin & Shaohui Zheng & Jiawang Xiao & Xinxin Xia & Xuanyao Yuan & Jingjing Zeng & Yu Shi & Yan Zhang & Hui Ma & Gaurav K. Varshney & Ji-Feng Fei & Yanmei Liu, 2024. "Cytosine base editors with increased PAM and deaminase motif flexibility for gene editing in zebrafish," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    19. Huawei Tong & Haoqiang Wang & Xuchen Wang & Nana Liu & Guoling Li & Danni Wu & Yun Li & Ming Jin & Hengbin Li & Yinghui Wei & Tong Li & Yuan Yuan & Linyu Shi & Xuan Yao & Yingsi Zhou & Hui Yang, 2024. "Development of deaminase-free T-to-S base editor and C-to-G base editor by engineered human uracil DNA glycosylase," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    20. Kun Jia & Yan-ru Cui & Shisheng Huang & Peihong Yu & Zhengxing Lian & Peixiang Ma & Jia Liu, 2022. "Phage peptides mediate precision base editing with focused targeting window," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36887-1. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.