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Targeted A-to-G base editing in human mitochondrial DNA with programmable deaminases

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Title
Targeted A-to-G base editing in human mitochondrial DNA with programmable deaminases
Author(s)
Sung-Ik Cho; Seonghyun Lee; Young Geun Mok; Kayeong Lim; Jaesuk Lee; Ji Min Lee; Eugene Chung; Jin-Soo Kim
Publication Date
2022-05
Journal
Cell, v.185, no.10, pp.1764 - 1776.e12
Publisher
Elsevier B.V.
Abstract
© 2022 The AuthorsMitochondrial 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%.
URI
https://pr.ibs.re.kr/handle/8788114/12260
DOI
10.1016/j.cell.2022.03.039
ISSN
0092-8674
Appears in Collections:
Center for Genome Engineering(유전체 교정 연구단) > 1. Journal Papers (저널논문)
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