Development of deaminase-free T-to-S base editor and C-to-G base editor by engineered human uracil DNA glycosylase

Huawei Tong (), Haoqiang Wang, Xuchen Wang, Nana Liu, Guoling Li, Danni Wu, Yun Li, Ming Jin, Hengbin Li, Yinghui Wei, Tong Li, Yuan Yuan, Linyu Shi, Xuan Yao, Yingsi Zhou () and Hui Yang ()
Additional contact information
Huawei Tong: Ltd.
Haoqiang Wang: Ltd.
Xuchen Wang: Chinese Academy of Sciences
Nana Liu: Ltd.
Guoling Li: Ltd.
Danni Wu: Ltd.
Yun Li: Ltd.
Ming Jin: Fujian Medical University
Hengbin Li: Ltd.
Yinghui Wei: Northwest A&F University
Tong Li: Ltd.
Yuan Yuan: Ltd.
Linyu Shi: Ltd.
Xuan Yao: Ltd.
Yingsi Zhou: Ltd.
Hui Yang: Ltd.

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract DNA base editors enable direct editing of adenine (A), cytosine (C), or guanine (G), but there is no base editor for direct thymine (T) editing currently. Here we develop two deaminase-free glycosylase-based base editors for direct T editing (gTBE) and C editing (gCBE) by fusing Cas9 nickase (nCas9) with engineered human uracil DNA glycosylase (UNG) variants. By several rounds of structure-informed rational mutagenesis on UNG in cultured human cells, we obtain gTBE and gCBE with high activity of T-to-S (i.e., T-to-C or T-to-G) and C-to-G conversions, respectively. Furthermore, we conduct parallel comparison of gTBE/gCBE with those recently developed using other protein engineering strategies, and find gTBE/gCBE show the outperformance. Thus, we provide several base editors, gTBEs and gCBEs, with corresponding engineered UNG variants, broadening the targeting scope of base editors.

Date: 2024
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DOI: 10.1038/s41467-024-49343-5

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