Targeted A-to-G base editing in human mitochondrial DNA with programmable deaminases.
Cell
; 185(10): 1764-1776.e12, 2022 05 12.
Article
en En
| MEDLINE
| ID: mdl-35472302
ABSTRACT
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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Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
ADN Mitocondrial
/
Enfermedades Mitocondriales
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cell
Año:
2022
Tipo del documento:
Article