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

Jin-Soo Kim’s team has discovered how to edit the mitochondrial genome to cure mitochondrial diseases. The first step was to adapt the basic editing system to induce C-to-T substitutions in mtDNA in mice because gene editing systems, such as CRISPR-Cas9, cannot edit mtDNA. Now the Kim lab has taken the next step: inducing A-to-G substitutions in mtDNA. Kim’s lab has adapted basic editing systems to edit the mitochondrial genome in mice, inducing pathogenic mutations in the ND5 gene via the C-to-T substitution. They did this using DddAtox which acts on double-stranded DNA and was originally used in mitochondrial cytosine base editing systems. Using their own genome-wide library of DNA-binding transcription activator-like effector proteins (TALEs), they created a system to induce C-to-T modifications by fusing the TALEs to split halves of DddAtox and an uracil glycosylase inhibitor. In this system, the TALE acts in the same way as a CRISPR sgRNA by directing the DddAtox enzyme to a target sequence. Now, the ability to also make A-to-G substitutions allows the theoretical correction of about 83% of pathogenic single nucleotide mutations in the mitochondrial genome. The implications of the study also extend to mitochondrial genetic variations related to cancer and diabetes.   

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