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Mok, Young Gun
유전체 교정 연구단
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Base editing in human cells with monomeric DddA-TALE fusion deaminases

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Title
Base editing in human cells with monomeric DddA-TALE fusion deaminases
Author(s)
Young Gun Mok; Ji Min Lee; Eugene Chung; Jaesuk Lee; Kayeong Lim; Sung-Ik Cho; Jin-Soo Kim
Publication Date
2022-07
Journal
Nature Communications, v.13, no.1
Publisher
Springer Science and Business Media LLC
Abstract
AbstractInter-bacterial toxin DddA-derived cytosine base editors (DdCBEs) enable targeted C-to-T conversions in nuclear and organellar DNA. DddAtox, the deaminase catalytic domain derived from Burkholderia cenocepacia, is split into two inactive halves to avoid its cytotoxicity in eukaryotic cells, when fused to transcription activator-like effector (TALE) DNA-binding proteins to make DdCBEs. As a result, DdCBEs function as pairs, which hampers gene delivery via viral vectors with a small cargo size. Here, we present non-toxic, full-length DddAtox variants to make monomeric DdCBEs (mDdCBEs), enabling mitochondrial DNA editing with high efficiencies of up to 50%, when transiently expressed in human cells. We demonstrate that mDdCBEs expressed via AAV in cultured human cells can achieve nearly homoplasmic C-to-T editing in mitochondrial DNA. Interestingly, mDdCBEs often produce mutation patterns different from those obtained with conventional dimeric DdCBEs. Furthermore, mDdCBEs allow base editing at sites for which only one TALE protein can be designed. We also show that transfection of mDdCBE-encoding mRNA, rather than plasmid, can reduce off-target editing in human mitochondrial DNA.
URI
https://pr.ibs.re.kr/handle/8788114/12007
DOI
10.1038/s41467-022-31745-y
ISSN
2041-1723
Appears in Collections:
Center for Genome Engineering(유전체 교정 연구단) > 1. Journal Papers (저널논문)
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