TadA orthologs enable both cytosine and adenine editing of base editors

Shuqian Zhang, Bo Yuan, Jixin Cao, Liting Song, Jinlong Chen, Jiayi Qiu, Zilong Qiu, Xing-Ming Zhao, Jingqi Chen and Tian-Lin Cheng ()
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Shuqian Zhang: Fudan 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
Xing-Ming Zhao: Fudan University
Jingqi Chen: Fudan University
Tian-Lin Cheng: Fudan University

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36003-3

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