Cited by 347CRISPR and Genetic EngineeringRNA regulation and diseaseEnzyme Catalysis and Immobilization

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Continuous evolution of base editors with expanded target compatibility and improved activity

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Thuronyi, B W., Koblan, Luke W., Levy, Jonathan M., Yeh, Wei-Hsi, Zheng, Christine, Newby, Gregory A., Wilson, Christopher, Bhaumik, Mantu, Shubina-Oleinik, Olga, Holt, Jeffrey R., Liu, David R.·2019·Nature Biotechnology

DOI 10.1038/s41587-019-0193-0PMC PMC6728210

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Abstract

Base editors use DNA-modifying enzymes targeted with a catalytically impaired CRISPR protein to precisely install point mutations. Here, we develop phage-assisted continuous evolution of base editors (BE-PACE) to improve their editing efficiency and target sequence compatibility. We used BE-PACE to evolve cytosine base editors (CBEs) that overcome target sequence context constraints of canonical CBEs. One evolved CBE, evoAPOBEC1-BE4max, is up to 26-fold more efficient at editing cytosine in the GC context, a disfavored context for wild-type APOBEC1 deaminase, while maintaining efficient editing in all other sequence contexts tested. Another evolved deaminase, evoFERNY, is 29% smaller than APOBEC1 and edits efficiently in all tested sequence contexts. We also evolved a CBE based on CDA1 deaminase with much higher editing efficiency at difficult target sites. Finally, we used data from evolved CBEs to illuminate the relationship between deaminase activity, base editing efficiency, editing window width and byproduct formation. These findings establish a system for rapid evolution of base editors and inform their use and improvement.

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Authors: Thuronyi, B. W., Koblan, L. W., Levy, J. M., Yeh, W.-H., Zheng, C., Newby, G. A., Wilson, C., Bhaumik, M., Shubina-Oleinik, O., Holt, J. R., & Liu, D. R.
Affiliations: Broad Institute (US)
Harvard University (US)
Boston Children's Hospital (US)
Corresponding author: Liu, David R.
ORCID: Thuronyi, B W.
Koblan, Luke W.
Levy, Jonathan M.
Yeh, Wei-Hsi
Zheng, Christine
Newby, Gregory A.
Wilson, Christopher
Bhaumik, Mantu
Shubina-Oleinik, Olga
Holt, Jeffrey R.
Liu, David R.
Venue: Nature Biotechnology
Publisher: Springer Science and Business Media LLC
Published: 2019-07-22
Volume: 37
Issue: 9
Pages: 1070-1079
ISSN: 0733-222X (ISSN-L)
1087-0156
1546-1696
DOI: 10.1038/s41587-019-0193-0
PMC: PMC6728210
OpenAlex: W2963629338
Cited by: 347
References: 65
Citations by year: 2026: 31 · 2025: 56 · 2024: 55 · 2023: 51 · 2022: 46 · 2021: 45 · 2020: 53 · 2019: 9
FWCI: 12.65
Type: journal article
Language: en
Update notices: correction (2019-08-12)
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature Biotechnology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion)
Funders: U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (U01 AI142756)
U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (RM1 HG009490)
U.S. Department of Health & Human Services | NIH | National Institute of Biomedical Imaging and Bioengineering (R01 EB022376)
U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (R35 GM118062)
United States Department of Defense | Defense Advanced Research Projects Agency (HR0011-17-2-0049)
Howard Hughes Medical Institute (Liu Investigatorship)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme Catalysis and Immobilization
Keywords: base editors, phage-assisted continuous evolution, cytosine base editors, editing efficiency, deaminase activity, by-product formation
MeSH terms: Gene Editing, Adenosine Deaminase, Animals, Base Sequence, Cell Line, Humans, Gene Expression Regulation, Enzymologic, Gene Targeting, Directed Molecular Evolution, Mice, INDEL Mutation, CRISPR-Cas Systems

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Continuous evolution of base editors with expanded target compatibility and improved activity

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