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An improved zinc-finger nuclease architecture for highly specific genome editing

Genome editing driven by zinc-finger nucleases (ZFNs) yields high gene-modification efficiencies (>10%) by introducing a recombinogenic double-strand break into the targeted gene. The cleavage event is induced using two custom-designed ZFNs that heterodimerize upon binding DNA to form a catalyticall... Full description

Journal Title: Nature biotechnology 2007-07, Vol.25 (7), p.778-785
Main Author: Wang, Jianbin
Other Authors: Rebar, Edward J , Guschin, Dmitry Y , Lee, Ya-Li , Holmes, Michael C , Miller, Jeffrey C , Gregory, Philip D , Kim, Kenneth A , Waite, Adam J , Beausejour, Christian M , Wang, Nathaniel S , Pabo, Carl O , Rupniewski, Igor
Format: Electronic Article Electronic Article
Language: English
Subjects:
DNA
Publisher: New York, NY: Nature Publishing Group
ID: ISSN: 1087-0156
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recordid: cdi_proquest_miscellaneous_70717381
title: An improved zinc-finger nuclease architecture for highly specific genome editing
format: Article
creator:
  • Wang, Jianbin
  • Rebar, Edward J
  • Guschin, Dmitry Y
  • Lee, Ya-Li
  • Holmes, Michael C
  • Miller, Jeffrey C
  • Gregory, Philip D
  • Kim, Kenneth A
  • Waite, Adam J
  • Beausejour, Christian M
  • Wang, Nathaniel S
  • Pabo, Carl O
  • Rupniewski, Igor
subjects:
  • Base Sequence
  • Binding Sites
  • Biological and medical sciences
  • Biotechnology
  • Biotechnology - methods
  • Catalysis
  • Deoxyribonucleases, Type II Site-Specific - chemistry
  • Deoxyribonucleic acid
  • Dimerization
  • DNA
  • Fundamental and applied biological sciences. Psychology
  • Genome
  • Genomics
  • Green Fluorescent Proteins - chemistry
  • Humans
  • Innovations
  • K562 Cells
  • Methods. Procedures. Technologies
  • Models, Biological
  • Molecular Conformation
  • Molecular Sequence Data
  • Protein engineering
  • Protein Structure, Tertiary
  • Technological change
  • Zinc
  • Zinc Fingers
ispartof: Nature biotechnology, 2007-07, Vol.25 (7), p.778-785
description: Genome editing driven by zinc-finger nucleases (ZFNs) yields high gene-modification efficiencies (>10%) by introducing a recombinogenic double-strand break into the targeted gene. The cleavage event is induced using two custom-designed ZFNs that heterodimerize upon binding DNA to form a catalytically active nuclease complex. Using the current ZFN architecture, however, cleavage-competent homodimers may also form that can limit safety or efficacy via off-target cleavage. Here we develop an improved ZFN architecture that eliminates this problem. Using structure-based design, we engineer two variant ZFNs that efficiently cleave DNA only when paired as a heterodimer. These ZFNs modify a native endogenous locus as efficiently as the parental architecture, but with a >40-fold reduction in homodimer function and much lower levels of genome-wide cleavage. This architecture provides a general means for improving the specificity of ZFNs as gene modification reagents.
language: eng
source:
identifier: ISSN: 1087-0156
fulltext: no_fulltext
issn:
  • 1087-0156
  • 1546-1696
url: Link


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titleAn improved zinc-finger nuclease architecture for highly specific genome editing
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descriptionGenome editing driven by zinc-finger nucleases (ZFNs) yields high gene-modification efficiencies (>10%) by introducing a recombinogenic double-strand break into the targeted gene. The cleavage event is induced using two custom-designed ZFNs that heterodimerize upon binding DNA to form a catalytically active nuclease complex. Using the current ZFN architecture, however, cleavage-competent homodimers may also form that can limit safety or efficacy via off-target cleavage. Here we develop an improved ZFN architecture that eliminates this problem. Using structure-based design, we engineer two variant ZFNs that efficiently cleave DNA only when paired as a heterodimer. These ZFNs modify a native endogenous locus as efficiently as the parental architecture, but with a >40-fold reduction in homodimer function and much lower levels of genome-wide cleavage. This architecture provides a general means for improving the specificity of ZFNs as gene modification reagents.
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subjectBase Sequence ; Binding Sites ; Biological and medical sciences ; Biotechnology ; Biotechnology - methods ; Catalysis ; Deoxyribonucleases, Type II Site-Specific - chemistry ; Deoxyribonucleic acid ; Dimerization ; DNA ; Fundamental and applied biological sciences. Psychology ; Genome ; Genomics ; Green Fluorescent Proteins - chemistry ; Humans ; Innovations ; K562 Cells ; Methods. Procedures. Technologies ; Models, Biological ; Molecular Conformation ; Molecular Sequence Data ; Protein engineering ; Protein Structure, Tertiary ; Technological change ; Zinc ; Zinc Fingers
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descriptionGenome editing driven by zinc-finger nucleases (ZFNs) yields high gene-modification efficiencies (>10%) by introducing a recombinogenic double-strand break into the targeted gene. The cleavage event is induced using two custom-designed ZFNs that heterodimerize upon binding DNA to form a catalytically active nuclease complex. Using the current ZFN architecture, however, cleavage-competent homodimers may also form that can limit safety or efficacy via off-target cleavage. Here we develop an improved ZFN architecture that eliminates this problem. Using structure-based design, we engineer two variant ZFNs that efficiently cleave DNA only when paired as a heterodimer. These ZFNs modify a native endogenous locus as efficiently as the parental architecture, but with a >40-fold reduction in homodimer function and much lower levels of genome-wide cleavage. This architecture provides a general means for improving the specificity of ZFNs as gene modification reagents.
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12Genomics
13Green Fluorescent Proteins - chemistry
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abstractGenome editing driven by zinc-finger nucleases (ZFNs) yields high gene-modification efficiencies (>10%) by introducing a recombinogenic double-strand break into the targeted gene. The cleavage event is induced using two custom-designed ZFNs that heterodimerize upon binding DNA to form a catalytically active nuclease complex. Using the current ZFN architecture, however, cleavage-competent homodimers may also form that can limit safety or efficacy via off-target cleavage. Here we develop an improved ZFN architecture that eliminates this problem. Using structure-based design, we engineer two variant ZFNs that efficiently cleave DNA only when paired as a heterodimer. These ZFNs modify a native endogenous locus as efficiently as the parental architecture, but with a >40-fold reduction in homodimer function and much lower levels of genome-wide cleavage. This architecture provides a general means for improving the specificity of ZFNs as gene modification reagents.
copNew York, NY
pubNature Publishing Group
pmid17603475
doi10.1038/nbt1319
tpages8