Broadening the targeting range of Staphylococcus aureus CRISPR-Cas9 by modifying PAM recognition
Open accessAbstract
CRISPR-Cas9 nucleases target specific DNA sequences using a guide RNA but also require recognition of a protospacer adjacent motif (PAM) by the Cas9 protein. Although longer PAMs can potentially improve the specificity of genome editing, they limit the range of sequences that Cas9 orthologs can target. One potential strategy to relieve this restriction is to relax the PAM recognition specificity of Cas9. Here we used molecular evolution to modify the NNGRRT PAM of Staphylococcus aureus Cas9 (SaCas9). One variant we identified, referred to as KKH SaCas9, showed robust genome editing activities at endogenous human target sites with NNNRRT PAMs, thereby increasing SaCas9 targeting range by two- to fourfold. Using GUIDE-seq, we show that wild-type and KKH SaCas9 induce comparable numbers of off-target effects in human cells. Our strategy for evolving PAM specificity does not require structural information and therefore should be applicable to a wide range of Cas9 orthologs.
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SaCas9 is about 1 kb shorter than SpCas9, but overall genetic size is still too large for application.
“Although the newly discovered Cas9 form from Staphylococcus aureus strain (SaCas9) is about 1 kb shorter than SpCas9, the overall genetic size is still too large for application [94, 140].”
From Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities (2018) · cites this paper as [140]
Due to recognition preference of some specific bases of CRISPR/Cas9 system and diverse epigenetic landscape, different targeted gene loci may exhibit distinctive different gene editing efficiencies.
“Besides, due to the recognition preference of some specific bases of CRISPR/Cas9 system and the diverse epigenetic landscape, different targeted gene loci may exhibit distinctive different gene editing efficiencies [140, 201–203].”
From Non-viral delivery systems for CRISPR/Cas9-based genome editing: challenges and opportunities (2018) · cites this paper as [140]
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Self-citation
- Authors
- Kleinstiver, B. P., Prew, M. S., Tsai, S. Q., Nguyen, N. T., Topkar, V. V., Zheng, Z., & Joung, J. K.
- Affiliations
- Harvard University (US)
- Massachusetts General Hospital (US)
- City University of Hong Kong (HK)
- Corresponding author
- Kleinstiver, Benjamin P
- Joung, J Keith
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2015-11-02
- Volume
- 33
- Issue
- 12
- Pages
- 1293-1298
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC4689141
- OpenAlex
- W1922040927
- Cited by
- 611
- References
- 34
- Citations by year
- 2026: 26 · 2025: 40 · 2024: 46 · 2023: 47 · 2022: 62 · 2021: 65 · 2020: 73 · 2019: 60 · 2018: 66 · 2017: 60 · 2016: 62 · 2015: 1 · 2014: 2 · 2013: 1
- FWCI
- 27.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (NIH-R01)
- Natural Sciences and Engineering Research Council of Canada
- National Institute of General Medical Sciences (DP1GM105378, R01GM107427)
- 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
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Keywords
- SaCas9, protospacer adjacent motif, PAM recognition, molecular evolution, genome editing, off-target effects, GUIDE-seq
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