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TadA orthologs enable both cytosine and adenine editing of base editors

Author

Listed:
  • Shuqian Zhang

    (Fudan University
    Qilu Hospital of Shandong University)

  • Bo Yuan

    (CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences)

  • Jixin Cao

    (Fudan University)

  • Liting Song

    (Fudan University)

  • Jinlong Chen

    (Fudan University)

  • Jiayi Qiu

    (Fudan University)

  • Zilong Qiu

    (CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences
    Fudan University
    Shanghai Jiao Tong University School of Medicine)

  • Xing-Ming Zhao

    (Fudan University
    Fudan University
    Fudan University)

  • Jingqi Chen

    (Fudan University
    Fudan University
    Fudan University)

  • Tian-Lin Cheng

    (Fudan University)

Abstract

Cytidine and adenosine deaminases are required for cytosine and adenine editing of base editors respectively, and no single deaminase could enable concurrent and comparable cytosine and adenine editing. Additionally, distinct properties of cytidine and adenosine deaminases lead to various types of off-target effects, including Cas9-indendepent DNA off-target effects for cytosine base editors (CBEs) and RNA off-target effects particularly severe for adenine base editors (ABEs). Here we demonstrate that 25 TadA orthologs could be engineered to generate functional ABEs, CBEs or ACBEs via single or double mutations, which display minimized Cas9-independent DNA off-target effects and genotoxicity, with orthologs B5ZCW4, Q57LE3, E8WVH3, Q13XZ4 and B3PCY2 as promising candidates for further engineering. Furthermore, RNA off-target effects of TadA ortholog-derived base editors could be further reduced or even eliminated by additional single mutation. Taken together, our work expands the base editing toolkits, and also provides important clues for the potential evolutionary process of deaminases.

Suggested Citation

  • Shuqian Zhang & Bo Yuan & Jixin Cao & Liting Song & Jinlong Chen & Jiayi Qiu & Zilong Qiu & Xing-Ming Zhao & Jingqi Chen & Tian-Lin Cheng, 2023. "TadA orthologs enable both cytosine and adenine editing of base editors," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36003-3
    DOI: 10.1038/s41467-023-36003-3
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    References listed on IDEAS

    as
    1. 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.
    2. Minh Thuan Nguyen Tran & Mohd Khairul Nizam Mohd Khalid & Qi Wang & Jacqueline K. R. Walker & Grace E. Lidgerwood & Kimberley L. Dilworth & Leszek Lisowski & Alice Pébay & Alex W. Hewitt, 2020. "Engineering domain-inlaid SaCas9 adenine base editors with reduced RNA off-targets and increased on-target DNA editing," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    3. Shuo Li & Bo Yuan & Jixin Cao & Jingqi Chen & Jinlong Chen & Jiayi Qiu & Xing-Ming Zhao & Xiaolin Wang & Zilong Qiu & Tian-Lin Cheng, 2020. "Docking sites inside Cas9 for adenine base editing diversification and RNA off-target elimination," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    4. 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.
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    1. 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.

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