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TadA 同源物使碱基编辑器能够进行胞嘧啶和腺嘌呤编辑。

TadA orthologs enable both cytosine and adenine editing of base editors.

机构信息

Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Institute of Pediatrics, National Children's Medical Center, Children's Hospital, Fudan University, Shanghai, China.

Department of Pediatrics, Qilu Hospital of Shandong University, Ji'nan, 250012, China.

出版信息

Nat Commun. 2023 Jan 26;14(1):414. doi: 10.1038/s41467-023-36003-3.

DOI:10.1038/s41467-023-36003-3
PMID:36702837
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9880001/
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.

摘要

胞苷脱氨酶和腺苷脱氨酶分别是碱基编辑器实现胞嘧啶和腺嘌呤编辑所必需的，而且没有单一的脱氨酶可以同时实现可比的胞嘧啶和腺嘌呤编辑。此外，胞苷脱氨酶和腺苷脱氨酶的不同特性导致了不同类型的脱靶效应，包括 CBEs 的 Cas9 独立的 DNA 脱靶效应和 ABEs 特别严重的 RNA 脱靶效应。在这里，我们证明了 25 种 TadA 同源物可以通过单个或双突变工程化生成功能性 ABEs、CBEs 或 ACBEs，它们显示出最小化的 Cas9 独立的 DNA 脱靶效应和遗传毒性，其中同源物 B5ZCW4、Q57LE3、E8WVH3、Q13XZ4 和 B3PCY2 是进一步工程化的有前途的候选物。此外，通过额外的单点突变可以进一步降低或甚至消除 TadA 同源物衍生碱基编辑器的 RNA 脱靶效应。总之，我们的工作扩展了碱基编辑工具包，也为脱氨酶的潜在进化过程提供了重要线索。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69a8/9880001/90ada7b6f40e/41467_2023_36003_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69a8/9880001/d34d3fb6f118/41467_2023_36003_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69a8/9880001/d87e679f6021/41467_2023_36003_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69a8/9880001/8e5683b6b59e/41467_2023_36003_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69a8/9880001/a0c60cd5beca/41467_2023_36003_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69a8/9880001/90ada7b6f40e/41467_2023_36003_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69a8/9880001/d34d3fb6f118/41467_2023_36003_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69a8/9880001/d87e679f6021/41467_2023_36003_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69a8/9880001/8e5683b6b59e/41467_2023_36003_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69a8/9880001/a0c60cd5beca/41467_2023_36003_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69a8/9880001/90ada7b6f40e/41467_2023_36003_Fig5_HTML.jpg

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引用本文的文献

[1]
High-precision cytosine base editors by evolving nucleic-acid-recognition hotspots in deaminase.

Nat Biotechnol. 2025-7-7

[2]
Charting the development and engineering of CRISPR base editors: lessons and inspirations.

Cell Chem Biol. 2025-6-19

[3]
Efforts to Downsize Base Editors for Clinical Applications.

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[4]
Engineering TadA ortholog-derived cytosine base editor without motif preference and adenosine activity limitation.

Nat Commun. 2024-9-16

[5]
Advancing CRISPR base editing technology through innovative strategies and ideas.

Sci China Life Sci. 2025-3

[6]
Zero-shot prediction of mutation effects with multimodal deep representation learning guides protein engineering.

Cell Res. 2024-9

[7]
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Nat Commun. 2024-5-10

[8]
Design and Engineering of Light-Induced Base Editors Facilitating Genome Editing with Enhanced Fidelity.

Adv Sci (Weinh). 2024-2

[9]
Engineering of cytosine base editors with DNA damage minimization and editing scope diversification.

Nucleic Acids Res. 2023-11-10

[10]
Amphioxus adenosine-to-inosine tRNA-editing enzyme that can perform C-to-U and A-to-I deamination of DNA.

Commun Biol. 2023-7-18

本文引用的文献

[1]
TadA reprogramming to generate potent miniature base editors with high precision.

Nat Commun. 2023-1-26

[2]
Evolution of an adenine base editor into a small, efficient cytosine base editor with low off-target activity.

Nat Biotechnol. 2023-5

[3]
Re-engineering the adenine deaminase TadA-8e for efficient and specific CRISPR-based cytosine base editing.

Nat Biotechnol. 2023-5

[4]
Functions and consequences of AID/APOBEC-mediated DNA and RNA deamination.

Nat Rev Genet. 2022-8

[5]
Controllable genome editing with split-engineered base editors.

Nat Chem Biol. 2021-12

[6]
Adenine base editor engineering reduces editing of bystander cytosines.

Nat Biotechnol. 2021-11

[7]
Structure-guided engineering of adenine base editor with minimized RNA off-targeting activity.

Nat Commun. 2021-4-16

[8]
A Cas-embedding strategy for minimizing off-target effects of DNA base editors.

Nat Commun. 2020-11-27

[9]
Docking sites inside Cas9 for adenine base editing diversification and RNA off-target elimination.

Nat Commun. 2020-11-17

[10]
Engineering domain-inlaid SaCas9 adenine base editors with reduced RNA off-targets and increased on-target DNA editing.

Nat Commun. 2020-9-25

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