生物
胞苷脱氨酶
线粒体DNA
胞嘧啶
胞苷
基因组编辑
胞嘧啶脱氨酶
RNA编辑
DNA
遗传学
生物化学
基因
分子生物学
清脆的
核糖核酸
酶
遗传增强
作者
Sung-Ik Cho,Seonghyun Lee,Young Geun Mok,Kayeong Lim,Jaesuk Lee,Ji Min Lee,Eugene Chung,Jin-Soo Kim
出处
期刊:Cell
[Elsevier]
日期:2022-05-01
卷期号:185 (10): 1764-1776.e12
被引量:99
标识
DOI:10.1016/j.cell.2022.03.039
摘要
Mitochondrial DNA (mtDNA) editing paves the way for disease modeling of mitochondrial genetic disorders in cell lines and animals and also for the treatment of these diseases in the future. Bacterial cytidine deaminase DddA-derived cytosine base editors (DdCBEs) enabling mtDNA editing, however, are largely limited to C-to-T conversions in the 5'-TC context (e.g., TC-to-TT conversions), suitable for generating merely 1/8 of all possible transition (purine-to-purine and pyrimidine-to-pyrimidine) mutations. Here, we present transcription-activator-like effector (TALE)-linked deaminases (TALEDs), composed of custom-designed TALE DNA-binding arrays, a catalytically impaired, full-length DddA variant or split DddA originated from Burkholderia cenocepacia, and an engineered deoxyadenosine deaminase derived from the E. coli TadA protein, which induce targeted A-to-G editing in human mitochondria. Custom-designed TALEDs were highly efficient in human cells, catalyzing A-to-G conversions at a total of 17 target sites in various mitochondrial genes with editing frequencies of up to 49%.
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