Engineering and optimising deaminase fusions for genome editing

Luhan Yang (), Adrian W. Briggs, Wei Leong Chew, Prashant Mali, Marc Guell, John Aach, Daniel Bryan Goodman, David Cox, Yinan Kan, Emal Lesha, Venkataramanan Soundararajan, Feng Zhang and George Church ()
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Luhan Yang: Harvard Medical School
Adrian W. Briggs: Harvard Medical School
Wei Leong Chew: Harvard Medical School
Prashant Mali: Harvard Medical School
Marc Guell: Harvard Medical School
John Aach: Harvard Medical School
Daniel Bryan Goodman: Harvard Medical School
David Cox: Harvard-MIT Division of Health Science and Technology
Yinan Kan: Harvard Medical School
Emal Lesha: Harvard Medical School
Venkataramanan Soundararajan: Harvard Medical School
Feng Zhang: Broad Institute of MIT and Harvard
George Church: Harvard Medical School

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: Abstract Precise editing is essential for biomedical research and gene therapy. Yet, homology-directed genome modification is limited by the requirements for genomic lesions, homology donors and the endogenous DNA repair machinery. Here we engineered programmable cytidine deaminases and test if we could introduce site-specific cytidine to thymidine transitions in the absence of targeted genomic lesions. Our programmable deaminases effectively convert specific cytidines to thymidines with 13% efficiency in Escherichia coli and 2.5% in human cells. However, off-target deaminations were detected more than 150 bp away from the target site. Moreover, whole genome sequencing revealed that edited bacterial cells did not harbour chromosomal abnormalities but demonstrated elevated global cytidine deamination at deaminase intrinsic binding sites. Therefore programmable deaminases represent a promising genome editing tool in prokaryotes and eukaryotes. Future engineering is required to overcome the processivity and the intrinsic DNA binding affinity of deaminases for safer therapeutic applications.

Date: 2016
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DOI: 10.1038/ncomms13330

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