利用 DddA-TALE 融合脱氨酶在小鼠中进行线粒体 DNA 编辑。
Mitochondrial DNA editing in mice with DddA-TALE fusion deaminases.
机构信息
Center for Genome Engineering, Institute for Basic Science, Daejeon, Republic of Korea.
Department of Chemistry, Seoul National University, Seoul, Republic of Korea.
出版信息
Nat Commun. 2021 Feb 19;12(1):1190. doi: 10.1038/s41467-021-21464-1.
DddA-derived cytosine base editors (DdCBEs), composed of the split interbacterial toxin DddA, transcription activator-like effector (TALE), and uracil glycosylase inhibitor (UGI), enable targeted C-to-T base conversions in mitochondrial DNA (mtDNA). Here, we demonstrate highly efficient mtDNA editing in mouse embryos using custom-designed DdCBEs. We target the mitochondrial gene, MT-ND5 (ND5), which encodes a subunit of NADH dehydrogenase that catalyzes NADH dehydration and electron transfer to ubiquinone, to obtain several mtDNA mutations, including m.G12918A associated with human mitochondrial diseases and m.C12336T that incorporates a premature stop codon, creating mitochondrial disease models in mice and demonstrating a potential for the treatment of mitochondrial disorders.
DddA 衍生的胞嘧啶碱基编辑器（DdCBEs）由分裂的细菌内毒素 DddA、转录激活因子样效应物（TALE）和尿嘧啶糖基化酶抑制剂（UGI）组成，可实现线粒体 DNA（mtDNA）中靶向 C 到 T 的碱基转换。在这里，我们使用定制设计的 DdCBE 在小鼠胚胎中展示了高效的 mtDNA 编辑。我们靶向线粒体基因 MT-ND5（ND5），该基因编码 NADH 脱氢酶的一个亚基，该酶催化 NADH 脱水和电子转移到泛醌，以获得几种 mtDNA 突变，包括与人类线粒体疾病相关的 m.G12918A 和 m.C12336T，它包含一个提前终止密码子，在小鼠中创建线粒体疾病模型，并展示了治疗线粒体疾病的潜力。
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