Fusion of catalytically inactive Cas9 to FokI nuclease improves the specificity of genome modification

A fusion of the FokI nuclease and a catalytically inactive Cas9 is a highly specific genome editing tool. Genome editing by Cas9, which cleaves double-stranded DNA at a sequence programmed by a short single-guide RNA (sgRNA), can result in off-target DNA modification that may be detrimental in some...

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Published in	Nature biotechnology Vol. 32; no. 6; pp. 577 - 582
Main Authors	Guilinger, John P, Thompson, David B, Liu, David R
Format	Journal Article
Language	English
Published	New York Nature Publishing Group US 01.06.2014 Nature Publishing Group
Subjects	631/1647/1511 Agriculture Bacterial Proteins - chemistry Bacterial Proteins - genetics Bioinformatics Biomedical Engineering/Biotechnology Biomedicine Biotechnology Clustered Regularly Interspaced Short Palindromic Repeats CRISPR-Associated Protein 9 CRISPR-Cas Systems Deoxyribonucleases, Type II Site-Specific - chemistry Deoxyribonucleases, Type II Site-Specific - genetics Deoxyribonucleic acid DNA Endonucleases - chemistry Endonucleases - genetics Gene Editing - methods Genetic engineering Genome, Human Genomics Humans Life Sciences Protein Multimerization Recombinant Fusion Proteins - chemistry Recombinant Fusion Proteins - genetics RNA - genetics
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Abstract	A fusion of the FokI nuclease and a catalytically inactive Cas9 is a highly specific genome editing tool. Genome editing by Cas9, which cleaves double-stranded DNA at a sequence programmed by a short single-guide RNA (sgRNA), can result in off-target DNA modification that may be detrimental in some applications. To improve DNA cleavage specificity, we generated fusions of catalytically inactive Cas9 and FokI nuclease (fCas9). DNA cleavage by fCas9 requires association of two fCas9 monomers that simultaneously bind target sites ∼15 or 25 base pairs apart. In human cells, fCas9 modified target DNA sites with >140-fold higher specificity than wild-type Cas9 and with an efficiency similar to that of paired Cas9 'nickases', recently engineered variants that cleave only one DNA strand per monomer. The specificity of fCas9 was at least fourfold higher than that of paired nickases at loci with highly similar off-target sites. Target sites that conform to the substrate requirements of fCas9 occur on average every 34 bp in the human genome, suggesting the versatility of this approach for highly specific genome-wide editing.
AbstractList	Genome editing by Cas9, which cleaves double-stranded DNA at a sequence programmed by a short single-guide RNA (sgRNA), can result in off-target DNA modification that may be detrimental in some applications. To improve DNA cleavage specificity, we generated fusions of catalytically inactive Cas9 and FokI nuclease (fCas9). DNA cleavage by fCas9 requires association of two fCas9 monomers that simultaneously bind target sites ∼15 or 25 base pairs apart. In human cells, fCas9 modified target DNA sites with >140-fold higher specificity than wild-type Cas9 and with an efficiency similar to that of paired Cas9 'nickases', recently engineered variants that cleave only one DNA strand per monomer. The specificity of fCas9 was at least fourfold higher than that of paired nickases at loci with highly similar off-target sites. Target sites that conform to the substrate requirements of fCas9 occur on average every 34 bp in the human genome, suggesting the versatility of this approach for highly specific genome-wide editing. A fusion of the FokI nuclease and a catalytically inactive Cas9 is a highly specific genome editing tool. Genome editing by Cas9, which cleaves double-stranded DNA at a sequence programmed by a short single-guide RNA (sgRNA), can result in off-target DNA modification that may be detrimental in some applications. To improve DNA cleavage specificity, we generated fusions of catalytically inactive Cas9 and FokI nuclease (fCas9). DNA cleavage by fCas9 requires association of two fCas9 monomers that simultaneously bind target sites ∼15 or 25 base pairs apart. In human cells, fCas9 modified target DNA sites with >140-fold higher specificity than wild-type Cas9 and with an efficiency similar to that of paired Cas9 'nickases', recently engineered variants that cleave only one DNA strand per monomer. The specificity of fCas9 was at least fourfold higher than that of paired nickases at loci with highly similar off-target sites. Target sites that conform to the substrate requirements of fCas9 occur on average every 34 bp in the human genome, suggesting the versatility of this approach for highly specific genome-wide editing. Genome editing by Cas9, which cleaves double-stranded DNA at a sequence programmed by a short single-guide RNA (sgRNA), can result in off-target DNA modification that may be detrimental in some applications. To improve DNA cleavage specificity, we generated fusions of catalytically inactive Cas9 and FokI nuclease (fCas9). DNA cleavage by fCas9 requires association of two fCas9 monomers that simultaneously bind target sites 15 or 25 base pairs apart. In human cells, fCas9 modified target DNA sites with >140-fold higher specificity than wild-type Cas9 and with an efficiency similar to that of paired Cas9 'nickases', recently engineered variants that cleave only one DNA strand per monomer. The specificity of fCas9 was at least fourfold higher than that of paired nickases at loci with highly similar off-target sites. Target sites that conform to the substrate requirements of fCas9 occur on average every 34 bp in the human genome, suggesting the versatility of this approach for highly specific genome-wide editing. Genome editing by Cas9, which cleaves double-stranded DNA at a sequence programmed by a short single-guide RNA (sgRNA), can result in off-target DNA modification that may be detrimental in some applications. To improve DNA cleavage specificity, we generated fusions of catalytically inactive Cas9 and FokI nuclease (fCas9). DNA cleavage by fCas9 requires association of two fCas9 monomers that simultaneously bind target sites ∼15 or 25 base pairs apart. In human cells, fCas9 modified target DNA sites with >140-fold higher specificity than wild-type Cas9 and with an efficiency similar to that of paired Cas9 'nickases', recently engineered variants that cleave only one DNA strand per monomer. The specificity of fCas9 was at least fourfold higher than that of paired nickases at loci with highly similar off-target sites. Target sites that conform to the substrate requirements of fCas9 occur on average every 34 bp in the human genome, suggesting the versatility of this approach for highly specific genome-wide editing.Genome editing by Cas9, which cleaves double-stranded DNA at a sequence programmed by a short single-guide RNA (sgRNA), can result in off-target DNA modification that may be detrimental in some applications. To improve DNA cleavage specificity, we generated fusions of catalytically inactive Cas9 and FokI nuclease (fCas9). DNA cleavage by fCas9 requires association of two fCas9 monomers that simultaneously bind target sites ∼15 or 25 base pairs apart. In human cells, fCas9 modified target DNA sites with >140-fold higher specificity than wild-type Cas9 and with an efficiency similar to that of paired Cas9 'nickases', recently engineered variants that cleave only one DNA strand per monomer. The specificity of fCas9 was at least fourfold higher than that of paired nickases at loci with highly similar off-target sites. Target sites that conform to the substrate requirements of fCas9 occur on average every 34 bp in the human genome, suggesting the versatility of this approach for highly specific genome-wide editing. Genome editing by Cas9, which cleaves double-stranded DNA at a sequence programmed by a short single-guide RNA (sgRNA), can result in off-target DNA modification that may be detrimental in some applications. To improve DNA cleavage specificity, we generated fusions of catalytically inactive Cas9 and Fok I nuclease (fCas9). DNA cleavage by fCas9 requires association of two fCas9 monomers that simultaneously bind target sites ~15 or 25 base pairs apart. In human cells, fCas9 modified target DNA sites with >140-fold higher specificity than wild-type Cas9 and with an efficiency similar to that of paired Cas9 ‘nickases’, recently engineered variants that cleave only one DNA strand per monomer. The specificity of fCas9 was at least 4-fold higher_than that of paired nickases at loci with highly similar off-target sites. Target sites that conform to the substrate requirements of fCas9 occur on average every 34 bp in the human genome, suggesting the broad versatility of this approach for highly specific genome-wide editing.
Author	Thompson, David B Guilinger, John P Liu, David R
AuthorAffiliation	2 Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA 1 Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA, USA
AuthorAffiliation_xml	– name: 1 Department of Chemistry & Chemical Biology, Harvard University, Cambridge, MA, USA – name: 2 Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA
Author_xml	– sequence: 1 givenname: John P surname: Guilinger fullname: Guilinger, John P organization: Department of Chemistry & Chemical Biology, Harvard University, Howard Hughes Medical Institute, Harvard University – sequence: 2 givenname: David B surname: Thompson fullname: Thompson, David B organization: Department of Chemistry & Chemical Biology, Harvard University, Howard Hughes Medical Institute, Harvard University – sequence: 3 givenname: David R surname: Liu fullname: Liu, David R email: drliu@fas.harvard.edu organization: Department of Chemistry & Chemical Biology, Harvard University, Howard Hughes Medical Institute, Harvard University
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/24770324$$D View this record in MEDLINE/PubMed
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Snippet	A fusion of the FokI nuclease and a catalytically inactive Cas9 is a highly specific genome editing tool. Genome editing by Cas9, which cleaves double-stranded... Genome editing by Cas9, which cleaves double-stranded DNA at a sequence programmed by a short single-guide RNA (sgRNA), can result in off-target DNA...
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SubjectTerms	631/1647/1511 Agriculture Bacterial Proteins - chemistry Bacterial Proteins - genetics Bioinformatics Biomedical Engineering/Biotechnology Biomedicine Biotechnology Clustered Regularly Interspaced Short Palindromic Repeats CRISPR-Associated Protein 9 CRISPR-Cas Systems Deoxyribonucleases, Type II Site-Specific - chemistry Deoxyribonucleases, Type II Site-Specific - genetics Deoxyribonucleic acid DNA Endonucleases - chemistry Endonucleases - genetics Gene Editing - methods Genetic engineering Genome, Human Genomics Humans Life Sciences Protein Multimerization Recombinant Fusion Proteins - chemistry Recombinant Fusion Proteins - genetics RNA - genetics
Title	Fusion of catalytically inactive Cas9 to FokI nuclease improves the specificity of genome modification
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