Engineering of high-precision base editors for site-specific single nucleotide replacement

Junjie Tan, Fei Zhang, Daniel Karcher and Ralph Bock ()
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Junjie Tan: Max-Planck-Institut für Molekulare Pflanzenphysiologie
Fei Zhang: Max-Planck-Institut für Molekulare Pflanzenphysiologie
Daniel Karcher: Max-Planck-Institut für Molekulare Pflanzenphysiologie
Ralph Bock: Max-Planck-Institut für Molekulare Pflanzenphysiologie

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract RNA-guided nucleases of the CRISPR/Cas type can be repurposed as programmable nucleotide deaminases to mediate targeted nucleotide substitutions. Such base editors have enormous potential in genome editing, gene therapy and precision breeding. However, current editors suffer from limited specificity in that they edit different and/or multiple bases within a larger sequence window. Using cytidine deaminase base editors that elicit C-to-T mutations, we show here that high editing precision can be achieved by engineering the connection between the deaminase domain and the Cas domain of the editor. By systematically testing different linker sequences and removing non-essential sequences from the deaminase, we obtain high-precision base editors with narrow activity windows that can selectively edit a single cytidine at a specific position with high accuracy and efficiency. These base editors will enable the use of genome editing in applications where single-nucleotide changes are required and off-target editing of adjacent nucleotides is not tolerable.

Date: 2019
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DOI: 10.1038/s41467-018-08034-8

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