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Efficient and high-fidelity base editor with expanded PAM compatibility for cytidine dinucleotide 被引量:5

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摘要 Cytidine base editor(CBE),which is composed of a cytidine deaminase fused to Cas9 nickase,has been widely used to induce C-to-T conversions in a wide range of organisms.However,the targeting scope of current CBEs is largely restricted to protospacer adjacent motif(PAM)sequences containing G,T,or A bases.In this study,we developed a new base editor termed“nNme2-CBE”with excellent PAM compatibility for cytidine dinucleotide,significantly expanding the genome-targeting scope of CBEs.Using nNme2-CBE,targeted editing efficiencies of 29.0%-55.0%and 17.3%—52.5%were generated in human cells and rabbit embryos,respectively.In contrast to conventional nSp-CBE,the nNme2-CBE is a natural high-fidelity base editing platform with minimal DNA off-targeting detected in vivo.Significantly increased efficiency in GC context and precision were determined by combining nNme2Cas9 with rationally engineered cytidine deaminases.In addition,the Founder rabbits with accurate single-base substitutions at Fgf5 gene loci were successfully generated by using the nNme2-CBE system.These novel nNme2-CBEs with expanded PAM compatibility and high fidelity will expand the base editing toolset for efficient gene modification and therapeutic applications.
出处 《Science China(Life Sciences)》 SCIE CAS CSCD 2021年第8期1355-1367,共13页 中国科学(生命科学英文版)
基金 financially supported by the National Key Research and Development Program of China Stem Cell and Translational Research (2019YFA0110700) the Program for Changjiang Scholars and Innovative Research Team in University (IRT16R32) the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16030501, XDA16030503) Key Research & Development Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory (2018GZR110104004)
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