期刊
CELL
卷 185, 期 10, 页码 1764-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2022.03.039
关键词
-
资金
- Institute for Basic Science [IBS-R021-D1]
Mitochondrial DNA editing is crucial for modeling mitochondrial genetic disorders and potential future treatments. This study presents a new editing enzyme called TALEDs, which efficiently induce A-to-G editing in human mitochondria.
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. coil 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 mitochondria' genes with editing frequencies of up to 49%.
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