Nuclear and mitochondrial DNA editing in human cells with zinc finger deaminases

Kayeong Lim, Sung-Ik Cho and Jin-Soo Kim ()
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Kayeong Lim: Institute for Basic Science
Sung-Ik Cho: Institute for Basic Science
Jin-Soo Kim: Institute for Basic Science

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract Base editing in nuclear DNA and mitochondrial DNA (mtDNA) is broadly useful for biomedical research, medicine, and biotechnology. Here, we present a base editing platform, termed zinc finger deaminases (ZFDs), composed of custom-designed zinc-finger DNA-binding proteins, the split interbacterial toxin deaminase DddAtox, and a uracil glycosylase inhibitor (UGI), which catalyze targeted C-to-T base conversions without inducing unwanted small insertions and deletions (indels) in human cells. We assemble plasmids encoding ZFDs using publicly available zinc finger resources to achieve base editing at frequencies of up to 60% in nuclear DNA and 30% in mtDNA. Because ZFDs, unlike CRISPR-derived base editors, do not cleave DNA to yield single- or double-strand breaks, no unwanted indels caused by error-prone non-homologous end joining are produced at target sites. Furthermore, recombinant ZFD proteins, expressed in and purified from E. coli, penetrate cultured human cells spontaneously to induce targeted base conversions, demonstrating the proof-of-principle of gene-free gene therapy.

Date: 2022
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DOI: 10.1038/s41467-022-27962-0

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