期刊
NATURE BIOTECHNOLOGY
卷 35, 期 4, 页码 371-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nbt.3803
关键词
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资金
- US National Institutes of Health (NIH) [R01 EB022376]
- NIH [R35GM118062]
- F-Prime Biomedical Research Initiative [A28161]
- Howard Hughes Medical Institute
- Ruth L. Kirchstein National Research Service Awards [F32 GM 112366-2]
- Natural Sciences and Engineering Research Council of Canada Postgraduate Scholarship (NSERC PGS-D)
- Harvard Biophysics NIH training grant [T32 GM008313]
Base editing induces single-nucleotide changes in the DNA of living cells using a fusion protein containing a catalytically defective Streptococcus pyogenes Cas9, a cytidine deaminase, and an inhibitor of base excision repair1. This genome editing approach has the advantage that it does not require formation of double-stranded DNA breaks or provision of a donor DNA template. Here we report the development of five C to T (or G to A) base editors that use natural and engineered Cas9 variants with different protospacer-adjacent motif (PAM) specificities to expand the number of sites that can be targeted by base editing 2.5-fold. Additionally, we engineered base editors containing mutated cytidine deaminase domains that narrow the width of the editing window from similar to 5 nucleotides to as little as 1-2 nucleotides. We thereby enabled discrimination of neighboring C nucleotides, which would otherwise be edited with similar efficiency, and doubled the number of disease-associated target Cs able to be corrected preferentially over nearby non-target Cs.
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