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Docking sites inside Cas9 for adenine base editing diversification and RNA off-target elimination

Author

Listed:
  • Shuo Li

    (Fudan University)

  • Bo Yuan

    (Chinese Academy of Sciences)

  • Jixin Cao

    (Fudan University)

  • Jingqi Chen

    (Fudan University)

  • Jinlong Chen

    (Fudan University)

  • Jiayi Qiu

    (Fudan University)

  • Xing-Ming Zhao

    (Fudan University)

  • Xiaolin Wang

    (Fudan University
    Shanghai Institute of Medical Imaging)

  • Zilong Qiu

    (Chinese Academy of Sciences
    Fudan University)

  • Tian-Lin Cheng

    (Fudan University)

Abstract

Base editing tools with diversified editing scopes and minimized RNA off-target activities are required for broad applications. Nevertheless, current Streptococcus pyogenes Cas9 (SpCas9)-based adenine base editors (ABEs) with minimized RNA off-target activities display constrained editing scopes with efficient editing activities at positions 4-8. Here, functional ABE variants with diversified editing scopes and reduced RNA off-target activities are identified using domain insertion profiling inside SpCas9 and with different combinations of TadA variants. Engineered ABE variants in this study display narrowed, expanded or shifted editing scopes with efficient editing activities across protospacer positions 2-16. And when combined with deaminase engineering, the RNA off-target activities of engineered ABE variants are further minimized. Thus, domain insertion profiling provides a framework to improve and expand ABE toolkits, and its combination with other strategies for ABE engineering deserves comprehensive explorations in the future.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19730-9
    DOI: 10.1038/s41467-020-19730-9
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    Cited by:

    1. 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.
    2. Nathan Bamidele & Han Zhang & Xiaolong Dong & Haoyang Cheng & Nicholas Gaston & Hailey Feinzig & Hanbing Cao & Karen Kelly & Jonathan K. Watts & Jun Xie & Guangping Gao & Erik J. Sontheimer, 2024. "Domain-inlaid Nme2Cas9 adenine base editors with improved activity and targeting scope," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. 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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