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
N1 - Publisher Copyright:
© 2023, The Author(s).
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 -
可持续发展目标 3 良好健康与福祉