Programmable DNA pyrimidine base editing via engineered uracil-DNA glycosylase

Zongyi Yi, Xiaoxue Zhang, Xiaoxu Wei, Jiayi Li, Jiwu Ren, Xue Zhang, Yike Zhang, Huixian Tang, Xiwen Chang, Ying Yu and Wensheng Wei ()
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Zongyi Yi: Peking University
Xiaoxue Zhang: Changping Laboratory
Xiaoxu Wei: Peking University
Jiayi Li: Peking University
Jiwu Ren: Changping Laboratory
Xue Zhang: Changping Laboratory
Yike Zhang: Peking University
Huixian Tang: Peking University
Xiwen Chang: Changping Laboratory
Ying Yu: Peking University
Wensheng Wei: Peking University

Nature Communications, 2024, vol. 15, issue 1, 1-10

Abstract: Abstract DNA base editing technologies predominantly utilize engineered deaminases, limiting their ability to edit thymine and guanine directly. In this study, we successfully achieve base editing of both cytidine and thymine by leveraging the translesion DNA synthesis pathway through the engineering of uracil-DNA glycosylase (UNG). Employing structure-based rational design, exploration of homologous proteins, and mutation screening, we identify a Deinococcus radiodurans UNG mutant capable of effectively editing thymine. When fused with the nickase Cas9, the engineered DrUNG protein facilitates efficient thymine base editing at endogenous sites, achieving editing efficiencies up to 55% without enrichment and exhibiting minimal cellular toxicity. This thymine base editor (TBE) exhibits high editing specificity and significantly restores IDUA enzyme activity in cells derived from patients with Hurler syndrome. TBEs represent efficient, specific, and low-toxicity approaches to base editing with potential applications in treating relevant diseases.

Date: 2024
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DOI: 10.1038/s41467-024-50012-w

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