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; Xiaohui Zhang

doi:10.1038/s41467-023-36887-1

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 ZhuMingyao Liu, Dali Li, Tao P. Zhong, Xiaohui Zhang

School of Life Sciences

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

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.

Original language	English
Article number	1224
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-36887-1
State	Published - Dec 2023

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Xue, N., Liu, X., Zhang, D., Wu, Y., Zhong, Y., Wang, J., Fan, W., Jiang, H., Zhu, B., Ge, X., Gonzalez, R. V. L., Chen, L., Zhang, S., She, P., Zhong, Z., Sun, J., Chen, X., Wang, L., Gu, Z., ... Zhang, X. (2023). Improving adenine and dual base editors through introduction of TadA-8e and Rad51DBD. Nature Communications, 14(1), Article 1224. https://doi.org/10.1038/s41467-023-36887-1

@article{e21ca18bc22c490781d97f310fe901ab,

title = "Improving adenine and dual base editors through introduction of TadA-8e and Rad51DBD",

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.",

author = "Niannian Xue and Xu Liu and Dan Zhang and Youming Wu and Yi Zhong and Jinxin Wang and Wenjing Fan and Haixia Jiang and Biyun Zhu and Xiyu Ge and Gonzalez, \{Rachel V.L.\} and Liang Chen and Shun Zhang and Peilu She and Zhilin Zhong and Jianjian Sun and Xi Chen and Liren Wang and Zhimin Gu and Ping Zhu and Mingyao Liu and Dali Li and Zhong, \{Tao P.\} and Xiaohui Zhang",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-36887-1",

language = "英语",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Xue, N, Liu, X, Zhang, D, Wu, Y, Zhong, Y, Wang, J, Fan, W, Jiang, H, Zhu, B, Ge, X, Gonzalez, RVL, Chen, L, Zhang, S, She, P, Zhong, Z, Sun, J, Chen, X, Wang, L, Gu, Z, Zhu, P, Liu, M , Li, D , Zhong, TP & Zhang, X 2023, 'Improving adenine and dual base editors through introduction of TadA-8e and Rad51DBD', Nature Communications, vol. 14, no. 1, 1224. https://doi.org/10.1038/s41467-023-36887-1

TY - JOUR

T1 - Improving adenine and dual base editors through introduction of TadA-8e and Rad51DBD

AU - Xue, Niannian

AU - Liu, Xu

AU - Zhang, Dan

AU - Wu, Youming

AU - Zhong, Yi

AU - Wang, Jinxin

AU - Fan, Wenjing

AU - Jiang, Haixia

AU - Zhu, Biyun

AU - Ge, Xiyu

AU - Gonzalez, Rachel V.L.

AU - Chen, Liang

AU - Zhang, Shun

AU - She, Peilu

AU - Zhong, Zhilin

AU - Sun, Jianjian

AU - Chen, Xi

AU - Wang, Liren

AU - Gu, Zhimin

AU - Zhu, Ping

AU - Liu, Mingyao

AU - Li, Dali

AU - Zhong, Tao P.

AU - Zhang, Xiaohui

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85149559394

U2 - 10.1038/s41467-023-36887-1

DO - 10.1038/s41467-023-36887-1

M3 - 文章

C2 - 36869044

AN - SCOPUS:85149559394

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1224

ER -

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

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