A dual A-to-Y and G-to-Y base editor and a four-base concurrent hypermutator in mammalian cells

Abstract Current dual base editors and hypermutators exhibit limited types of base conversion and constrained mutational diversity. To address this challenge, we engineer a compact dual base editor “A&GBE” by fusing a deaminase and glycosylase with nickase Cas9 (nCas9) to enable concurrent adenine and cytosine editing. Furthermore, we develop quadruple base mutating modules (QBMM) by fusing nickase or dead Cas9 with engineered thymine-DNA glycosylase (TDG), N-methylpurine DNA glycosylase (MPG) and TadA8e, together with MS2-MCP system recruited activation-induced cytidine deaminase (AID). This QBMM enables simultaneous mutation of all four types of nucleotide bases (A, T, G, C) within an approximately 100 base pair (bp) sequence surrounding the gRNA target site. This platform generates hyper diverse multi-nucleotide variants, establishing a powerful tool for accelerated protein evolution, functional genomics, and disease modeling.

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Publication Details

Journal
Nature Communications
Published
2026-08-27
DOI
https://doi.org/10.1038/s41467-026-77241-5
Primary Topic
CRISPR and Genetic Engineering
Type
article
Field-Weighted Citation Impact
0.00

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article

A dual A-to-Y and G-to-Y base editor and a four-base concurrent hypermutator in mammalian cells

Xiaotian Huang, Xiaoxia Shi, Zongliang Gao, Feilong Ou et al.
Nature Communications
CRISPR and Genetic Engineering
article

A dual A-to-Y and G-to-Y base editor and a four-base concurrent hypermutator in mammalian cells

Xiaotian Huang, Xiaoxia Shi, Zongliang Gao, Feilong Ou, Na Zhao, Junyun Huang, Joshua Seun Olajide, 邹秀斌, Gang Wang, Jiejing Lin, Tianfu Tao, Tinghai Zhou, Zemin Ren, Zhihong Guan
article en

Abstract

Abstract Current dual base editors and hypermutators exhibit limited types of base conversion and constrained mutational diversity. To address this challenge, we engineer a compact dual base editor “A&GBE” by fusing a deaminase and glycosylase with nickase Cas9 (nCas9) to enable concurrent adenine and cytosine editing. Furthermore, we develop quadruple base mutating modules (QBMM) by fusing nickase or dead Cas9 with engineered thymine-DNA glycosylase (TDG), N-methylpurine DNA glycosylase (MPG) and TadA8e, together with MS2-MCP system recruited activation-induced cytidine deaminase (AID). This QBMM enables simultaneous mutation of all four types of nucleotide bases (A, T, G, C) within an approximately 100 base pair (bp) sequence surrounding the gRNA target site. This platform generates hyper diverse multi-nucleotide variants, establishing a powerful tool for accelerated protein evolution, functional genomics, and disease modeling.

Nature Communications
Jiangnan University (CN), Nanchang University (CN), Liaoning Normal University (CN), Guangzhou University (CN), Second Affiliated Hospital of Nanchang University (CN), Gannan Medical University (CN), First Affiliated Hospital of Gannan Medical University (CN), Guangzhou Electronic Technology (China) (CN), Guangzhou Medical University (CN)
National Natural Science Foundation of China, Natural Science Foundation of Jiangxi Province, Guangzhou University, Gannan Medical University
Openalex Percentile: Top 17%
CRISPR and Genetic Engineering
DOIOpen Access PDFOpenAlex
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