Structure-based redesign of the dimerization interface reduces the toxicity of zinc-finger nucleases View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2007-07

AUTHORS

Michal Szczepek, Vincent Brondani, Janine Büchel, Luis Serrano, David J Segal, Toni Cathomen

ABSTRACT

Artificial endonucleases consisting of a FokI cleavage domain tethered to engineered zinc-finger DNA-binding proteins have proven useful for stimulating homologous recombination in a variety of cell types. Because the catalytic domain of zinc-finger nucleases (ZFNs) must dimerize to become active, two subunits are typically assembled as heterodimers at the cleavage site. The use of ZFNs is often associated with significant cytotoxicity, presumably due to cleavage at off-target sites. Here we describe a structure-based approach to reducing off-target cleavage. Using in silico protein modeling and energy calculations, we increased the specificity of target site cleavage by preventing homodimerization and lowering the dimerization energy. Cell-based recombination assays confirmed that the modified ZFNs were as active as the original ZFNs but elicit significantly less genotoxicity. The improved safety profile may facilitate therapeutic application of the ZFN technology. More... »

PAGES

786-793

Journal

TITLE

Nature Biotechnology

ISSUE

7

VOLUME

25

Author Affiliations

Related Patents

  • Method For Making Antibody Fc-Heterodimeric Molecules Using Electrostatic Steering Effects
  • Engineered Transcription Activator-Like Effector (Tale) Domains And Uses Thereof
  • Methods For Correcting Presenilin Point Mutations
  • In Vivo Determination Of The Lokalization Of Dna Double-Stand Breaks And Application Thereof
  • Engineered Crispr-Cas9 Nucleases
  • Using Rna-Guided Foki Nucleases (Rfns) To Increase Specificity For Rna-Guided Genome Editing
  • Method For Making Antibody Fc-Heterodimeric Molecules Using Electrostatic Steering Effects
  • Methods For Nucleic Acid Editing
  • Rationally-Designed Meganuclease Variants Of Lig-34 And I-Crei For Maize Genome Engineering
  • Evaluation And Improvement Of Nuclease Cleavage Specificity
  • Cas9 Proteins Including Ligand-Dependent Inteins
  • Compositions And Methods For Site Specific Recombination At Asymmetric Sites
  • Using Truncated Guide Rnas (Tru-Grnas) To Increase Specificity For Rna-Guided Genome Editing
  • Engineered Cleavage Half-Domains
  • Using Rna-Guided Foki Nucleases (Rfns) To Increase Specificity For Rna-Guided Genome Editing
  • Engineered Cleavage Half-Domains
  • Crispr-Related Methods And Compositions With Governing Grnas
  • Stable And Aggregation Free Antibody Fc Molecules Through Ch3 Domain Interface Engineering
  • Increasing Specificity For Rna-Guided Genome Editing
  • Methods For Identifying A Target Site Of A Cas9 Nuclease
  • Zinc Finger Nuclease For The Cftr Gene And Methods Of Use Thereof
  • Crispr/Cas-Related Methods And Compositions For Treating Leber's Congenital Amaurosis 10 (Lca10)
  • Engineered Crispr-Cas9 Nucleases
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nbt1317

    DOI

    http://dx.doi.org/10.1038/nbt1317

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1045480104

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/17603476


    Indexing Status Check whether this publication has been indexed by Scopus and Web Of Science using the SN Indexing Status Tool
    Incoming Citations Browse incoming citations for this publication using opencitations.net

    JSON-LD is the canonical representation for SciGraph data.

    TIP: You can open this SciGraph record using an external JSON-LD service: JSON-LD Playground Google SDTT

    [
      {
        "@context": "https://springernature.github.io/scigraph/jsonld/sgcontext.json", 
        "about": [
          {
            "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/0601", 
            "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
            "name": "Biochemistry and Cell Biology", 
            "type": "DefinedTerm"
          }, 
          {
            "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/06", 
            "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
            "name": "Biological Sciences", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Amino Acid Sequence", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Base Sequence", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Biotechnology", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Catalytic Domain", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Cell Line", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Cell Line, Tumor", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Codon, Terminator", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Deoxyribonucleases, Type II Site-Specific", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Dimerization", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Humans", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Molecular Sequence Data", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Protein Conformation", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Recombination, Genetic", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Sequence Homology, Amino Acid", 
            "type": "DefinedTerm"
          }, 
          {
            "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
            "name": "Zinc Fingers", 
            "type": "DefinedTerm"
          }
        ], 
        "author": [
          {
            "affiliation": {
              "alternateName": "Freie Universit\u00e4t Berlin", 
              "id": "https://www.grid.ac/institutes/grid.14095.39", 
              "name": [
                "Charit\u00e9 Medical School, Institute of Virology (CBF), 12203 Berlin, Germany."
              ], 
              "type": "Organization"
            }, 
            "familyName": "Szczepek", 
            "givenName": "Michal", 
            "type": "Person"
          }, 
          {
            "familyName": "Brondani", 
            "givenName": "Vincent", 
            "id": "sg:person.01056624027.62", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01056624027.62"
            ], 
            "type": "Person"
          }, 
          {
            "familyName": "B\u00fcchel", 
            "givenName": "Janine", 
            "id": "sg:person.0704613520.44", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0704613520.44"
            ], 
            "type": "Person"
          }, 
          {
            "familyName": "Serrano", 
            "givenName": "Luis", 
            "type": "Person"
          }, 
          {
            "familyName": "Segal", 
            "givenName": "David J", 
            "id": "sg:person.01044507752.93", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01044507752.93"
            ], 
            "type": "Person"
          }, 
          {
            "familyName": "Cathomen", 
            "givenName": "Toni", 
            "id": "sg:person.0717175012.11", 
            "sameAs": [
              "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0717175012.11"
            ], 
            "type": "Person"
          }
        ], 
        "citation": [
          {
            "id": "https://doi.org/10.1073/pnas.93.3.1156", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1001210891"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1093/nar/gkl076", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1001212823"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1083/jcb.146.5.905", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1001594320"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1083/jcb.146.5.905", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1001594320"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1128/mcb.23.10.3550-3557.2003", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1002760154"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1126/science.1078395", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1003888273"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1006/jmbi.1998.1747", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1007956468"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/40446", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1008028344", 
              "https://doi.org/10.1038/40446"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/40446", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1008028344", 
              "https://doi.org/10.1038/40446"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nbt794", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1008187948", 
              "https://doi.org/10.1038/nbt794"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nbt794", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1008187948", 
              "https://doi.org/10.1038/nbt794"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1073/pnas.0510187103", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1011497430"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1016/s0022-2836(02)00442-4", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1013603912"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1534/genetics.105.052829", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1014430276"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1534/genetics.105.052829", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1014430276"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1093/nar/gkg375", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1016134561"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1128/mcb.21.1.289-297.2001", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1019605954"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1074/jbc.272.45.28545", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1020122890"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1074/jbc.m110669200", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1020428610"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1128/mcb.14.12.8096", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1022051171"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1073/pnas.95.18.10570", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1022863238"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1016/j.ymthe.2005.06.094", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1023502951"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1016/j.jmb.2005.10.050", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1023503877"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1093/nar/23.24.5012", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1024116167"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1074/jbc.m102604200", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1026702498"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1073/pnas.0506124102", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1031394506"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1128/mcb.15.4.1968", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1034391289"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1073/pnas.0501980102", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1035557908"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1073/pnas.0501980102", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1035557908"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1073/pnas.111009698", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1036799989"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1073/pnas.2135381100", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1036939244"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1073/pnas.95.18.10564", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1037239563"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1385/1-59745-116-9:207", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1037986294", 
              "https://doi.org/10.1385/1-59745-116-9:207"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1074/jbc.m506654200", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1038367262"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1074/jbc.m506654200", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1038367262"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1128/mcb.17.1.267", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1039424106"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nature03556", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1040117781", 
              "https://doi.org/10.1038/nature03556"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "sg:pub.10.1038/nature03556", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1040117781", 
              "https://doi.org/10.1038/nature03556"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1074/jbc.273.10.5858", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1040536653"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1128/mcb.23.10.3558-3565.2003", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1040854262"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1128/jvi.74.23.11407-11412.2000", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1041857462"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1073/pnas.96.6.2758", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1043463987"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1016/j.ymthe.2005.08.003", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1043579457"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1016/j.ymthe.2005.08.003", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1043579457"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1016/j.jmb.2006.06.063", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1043647943"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1126/science.1134833", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1044417952"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1093/nar/28.17.3361", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1051444401"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1016/j.jmb.2005.10.010", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1051974502"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1016/j.jmb.2005.10.010", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1051974502"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://doi.org/10.1667/rr3516.1", 
            "sameAs": [
              "https://app.dimensions.ai/details/publication/pub.1068196612"
            ], 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://app.dimensions.ai/details/publication/pub.1075329244", 
            "type": "CreativeWork"
          }, 
          {
            "id": "https://app.dimensions.ai/details/publication/pub.1077293533", 
            "type": "CreativeWork"
          }
        ], 
        "datePublished": "2007-07", 
        "datePublishedReg": "2007-07-01", 
        "description": "Artificial endonucleases consisting of a FokI cleavage domain tethered to engineered zinc-finger DNA-binding proteins have proven useful for stimulating homologous recombination in a variety of cell types. Because the catalytic domain of zinc-finger nucleases (ZFNs) must dimerize to become active, two subunits are typically assembled as heterodimers at the cleavage site. The use of ZFNs is often associated with significant cytotoxicity, presumably due to cleavage at off-target sites. Here we describe a structure-based approach to reducing off-target cleavage. Using in silico protein modeling and energy calculations, we increased the specificity of target site cleavage by preventing homodimerization and lowering the dimerization energy. Cell-based recombination assays confirmed that the modified ZFNs were as active as the original ZFNs but elicit significantly less genotoxicity. The improved safety profile may facilitate therapeutic application of the ZFN technology.", 
        "genre": "research_article", 
        "id": "sg:pub.10.1038/nbt1317", 
        "inLanguage": [
          "en"
        ], 
        "isAccessibleForFree": true, 
        "isFundedItemOf": [
          {
            "id": "sg:grant.2603762", 
            "type": "MonetaryGrant"
          }
        ], 
        "isPartOf": [
          {
            "id": "sg:journal.1115214", 
            "issn": [
              "1087-0156", 
              "1546-1696"
            ], 
            "name": "Nature Biotechnology", 
            "type": "Periodical"
          }, 
          {
            "issueNumber": "7", 
            "type": "PublicationIssue"
          }, 
          {
            "type": "PublicationVolume", 
            "volumeNumber": "25"
          }
        ], 
        "name": "Structure-based redesign of the dimerization interface reduces the toxicity of zinc-finger nucleases", 
        "pagination": "786-793", 
        "productId": [
          {
            "name": "readcube_id", 
            "type": "PropertyValue", 
            "value": [
              "d8a40e8a66c2924ad48f01a6d45b33440b250e63d32e17a3e8d9036b0b4934f2"
            ]
          }, 
          {
            "name": "pubmed_id", 
            "type": "PropertyValue", 
            "value": [
              "17603476"
            ]
          }, 
          {
            "name": "nlm_unique_id", 
            "type": "PropertyValue", 
            "value": [
              "9604648"
            ]
          }, 
          {
            "name": "doi", 
            "type": "PropertyValue", 
            "value": [
              "10.1038/nbt1317"
            ]
          }, 
          {
            "name": "dimensions_id", 
            "type": "PropertyValue", 
            "value": [
              "pub.1045480104"
            ]
          }
        ], 
        "sameAs": [
          "https://doi.org/10.1038/nbt1317", 
          "https://app.dimensions.ai/details/publication/pub.1045480104"
        ], 
        "sdDataset": "articles", 
        "sdDatePublished": "2019-04-11T00:55", 
        "sdLicense": "https://scigraph.springernature.com/explorer/license/", 
        "sdPublisher": {
          "name": "Springer Nature - SN SciGraph project", 
          "type": "Organization"
        }, 
        "sdSource": "s3://com-uberresearch-data-dimensions-target-20181106-alternative/cleanup/v134/2549eaecd7973599484d7c17b260dba0a4ecb94b/merge/v9/a6c9fde33151104705d4d7ff012ea9563521a3ce/jats-lookup/v90/0000000001_0000000264/records_8697_00000426.jsonl", 
        "type": "ScholarlyArticle", 
        "url": "http://www.nature.com/nbt/journal/v25/n7/full/nbt1317.html"
      }
    ]
     

    Download the RDF metadata as:  json-ld nt turtle xml License info

    HOW TO GET THIS DATA PROGRAMMATICALLY:

    JSON-LD is a popular format for linked data which is fully compatible with JSON.

    curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/pub.10.1038/nbt1317'

    N-Triples is a line-based linked data format ideal for batch operations.

    curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1038/nbt1317'

    Turtle is a human-readable linked data format.

    curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1038/nbt1317'

    RDF/XML is a standard XML format for linked data.

    curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1038/nbt1317'


     

    This table displays all metadata directly associated to this object as RDF triples.

    290 TRIPLES      21 PREDICATES      87 URIs      36 LITERALS      24 BLANK NODES

    Subject Predicate Object
    1 sg:pub.10.1038/nbt1317 schema:about N0b2c9b229bd24f679322ac60c1e41da7
    2 N11f9409270924a43a181b98c25f917a1
    3 N3b323ec1685e48c3baad5a1823a77e18
    4 N4dead122cabb4c74b79abe5cb2221aca
    5 N5bfe838837e2402bb58c6165f27aa780
    6 N5cc90343c645457985ecf82647e76b03
    7 N7a006690c9bf45f79e3bfeedade9324c
    8 N7e12325270b843a7bf4e4c17313e0c47
    9 N8120eaadfdaf45c7aacb628d480f16a2
    10 N81e2058035df4693a2d485cc03e55d5e
    11 Nb2933f00237342f99992865a8e7d41b7
    12 Nc160b51024f744fe98179cd8b309cecc
    13 Nf49859cbd09e4b1092b8fc7cda40de35
    14 Nfccbed05c0934c62b4078aa988e1c60e
    15 Nfdaea91a92d8486eae20f37f2fe36cd1
    16 anzsrc-for:06
    17 anzsrc-for:0601
    18 schema:author N4c86d366a1dc4909b2a70d91cfe4614b
    19 schema:citation sg:pub.10.1038/40446
    20 sg:pub.10.1038/nature03556
    21 sg:pub.10.1038/nbt794
    22 sg:pub.10.1385/1-59745-116-9:207
    23 https://app.dimensions.ai/details/publication/pub.1075329244
    24 https://app.dimensions.ai/details/publication/pub.1077293533
    25 https://doi.org/10.1006/jmbi.1998.1747
    26 https://doi.org/10.1016/j.jmb.2005.10.010
    27 https://doi.org/10.1016/j.jmb.2005.10.050
    28 https://doi.org/10.1016/j.jmb.2006.06.063
    29 https://doi.org/10.1016/j.ymthe.2005.06.094
    30 https://doi.org/10.1016/j.ymthe.2005.08.003
    31 https://doi.org/10.1016/s0022-2836(02)00442-4
    32 https://doi.org/10.1073/pnas.0501980102
    33 https://doi.org/10.1073/pnas.0506124102
    34 https://doi.org/10.1073/pnas.0510187103
    35 https://doi.org/10.1073/pnas.111009698
    36 https://doi.org/10.1073/pnas.2135381100
    37 https://doi.org/10.1073/pnas.93.3.1156
    38 https://doi.org/10.1073/pnas.95.18.10564
    39 https://doi.org/10.1073/pnas.95.18.10570
    40 https://doi.org/10.1073/pnas.96.6.2758
    41 https://doi.org/10.1074/jbc.272.45.28545
    42 https://doi.org/10.1074/jbc.273.10.5858
    43 https://doi.org/10.1074/jbc.m102604200
    44 https://doi.org/10.1074/jbc.m110669200
    45 https://doi.org/10.1074/jbc.m506654200
    46 https://doi.org/10.1083/jcb.146.5.905
    47 https://doi.org/10.1093/nar/23.24.5012
    48 https://doi.org/10.1093/nar/28.17.3361
    49 https://doi.org/10.1093/nar/gkg375
    50 https://doi.org/10.1093/nar/gkl076
    51 https://doi.org/10.1126/science.1078395
    52 https://doi.org/10.1126/science.1134833
    53 https://doi.org/10.1128/jvi.74.23.11407-11412.2000
    54 https://doi.org/10.1128/mcb.14.12.8096
    55 https://doi.org/10.1128/mcb.15.4.1968
    56 https://doi.org/10.1128/mcb.17.1.267
    57 https://doi.org/10.1128/mcb.21.1.289-297.2001
    58 https://doi.org/10.1128/mcb.23.10.3550-3557.2003
    59 https://doi.org/10.1128/mcb.23.10.3558-3565.2003
    60 https://doi.org/10.1534/genetics.105.052829
    61 https://doi.org/10.1667/rr3516.1
    62 schema:datePublished 2007-07
    63 schema:datePublishedReg 2007-07-01
    64 schema:description Artificial endonucleases consisting of a FokI cleavage domain tethered to engineered zinc-finger DNA-binding proteins have proven useful for stimulating homologous recombination in a variety of cell types. Because the catalytic domain of zinc-finger nucleases (ZFNs) must dimerize to become active, two subunits are typically assembled as heterodimers at the cleavage site. The use of ZFNs is often associated with significant cytotoxicity, presumably due to cleavage at off-target sites. Here we describe a structure-based approach to reducing off-target cleavage. Using in silico protein modeling and energy calculations, we increased the specificity of target site cleavage by preventing homodimerization and lowering the dimerization energy. Cell-based recombination assays confirmed that the modified ZFNs were as active as the original ZFNs but elicit significantly less genotoxicity. The improved safety profile may facilitate therapeutic application of the ZFN technology.
    65 schema:genre research_article
    66 schema:inLanguage en
    67 schema:isAccessibleForFree true
    68 schema:isPartOf Nc8fa25d341e6494987e35abb55f14b94
    69 Nd2b0cb6648004811ba9aedd8ce3055c6
    70 sg:journal.1115214
    71 schema:name Structure-based redesign of the dimerization interface reduces the toxicity of zinc-finger nucleases
    72 schema:pagination 786-793
    73 schema:productId N32be669cc4c64b0c9f5356231b1f3720
    74 N3efd6b86c8c24afa8cc1b50ced5daefe
    75 N60bc99a11e914cf88b2cddc61501fcc5
    76 N65f9a38b7a344905afe2726d97b467a0
    77 Na2817f9506ed44e1bce17ebb63146fd7
    78 schema:sameAs https://app.dimensions.ai/details/publication/pub.1045480104
    79 https://doi.org/10.1038/nbt1317
    80 schema:sdDatePublished 2019-04-11T00:55
    81 schema:sdLicense https://scigraph.springernature.com/explorer/license/
    82 schema:sdPublisher N7f31e3f44fb0490bb971e2391f95cb7e
    83 schema:url http://www.nature.com/nbt/journal/v25/n7/full/nbt1317.html
    84 sgo:license sg:explorer/license/
    85 sgo:sdDataset articles
    86 rdf:type schema:ScholarlyArticle
    87 N081839583e404dfda62f8cd9992febee rdf:first sg:person.01056624027.62
    88 rdf:rest N56fde76d8ec247ffb83b028175e369f1
    89 N0b2c9b229bd24f679322ac60c1e41da7 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    90 schema:name Humans
    91 rdf:type schema:DefinedTerm
    92 N11f9409270924a43a181b98c25f917a1 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    93 schema:name Deoxyribonucleases, Type II Site-Specific
    94 rdf:type schema:DefinedTerm
    95 N32be669cc4c64b0c9f5356231b1f3720 schema:name dimensions_id
    96 schema:value pub.1045480104
    97 rdf:type schema:PropertyValue
    98 N3b323ec1685e48c3baad5a1823a77e18 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    99 schema:name Protein Conformation
    100 rdf:type schema:DefinedTerm
    101 N3efd6b86c8c24afa8cc1b50ced5daefe schema:name readcube_id
    102 schema:value d8a40e8a66c2924ad48f01a6d45b33440b250e63d32e17a3e8d9036b0b4934f2
    103 rdf:type schema:PropertyValue
    104 N4c86d366a1dc4909b2a70d91cfe4614b rdf:first Ne47c6d0b44b64f8aaa7d31c1c35819f5
    105 rdf:rest N081839583e404dfda62f8cd9992febee
    106 N4dead122cabb4c74b79abe5cb2221aca schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    107 schema:name Dimerization
    108 rdf:type schema:DefinedTerm
    109 N56fde76d8ec247ffb83b028175e369f1 rdf:first sg:person.0704613520.44
    110 rdf:rest Ndc5d52220bfe4b2b8d47e1ba75704e04
    111 N5bfe838837e2402bb58c6165f27aa780 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    112 schema:name Cell Line
    113 rdf:type schema:DefinedTerm
    114 N5cc90343c645457985ecf82647e76b03 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    115 schema:name Molecular Sequence Data
    116 rdf:type schema:DefinedTerm
    117 N60bc99a11e914cf88b2cddc61501fcc5 schema:name doi
    118 schema:value 10.1038/nbt1317
    119 rdf:type schema:PropertyValue
    120 N65f9a38b7a344905afe2726d97b467a0 schema:name pubmed_id
    121 schema:value 17603476
    122 rdf:type schema:PropertyValue
    123 N7a006690c9bf45f79e3bfeedade9324c schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    124 schema:name Codon, Terminator
    125 rdf:type schema:DefinedTerm
    126 N7e12325270b843a7bf4e4c17313e0c47 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    127 schema:name Recombination, Genetic
    128 rdf:type schema:DefinedTerm
    129 N7f31e3f44fb0490bb971e2391f95cb7e schema:name Springer Nature - SN SciGraph project
    130 rdf:type schema:Organization
    131 N8120eaadfdaf45c7aacb628d480f16a2 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    132 schema:name Base Sequence
    133 rdf:type schema:DefinedTerm
    134 N81e2058035df4693a2d485cc03e55d5e schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    135 schema:name Amino Acid Sequence
    136 rdf:type schema:DefinedTerm
    137 Na2817f9506ed44e1bce17ebb63146fd7 schema:name nlm_unique_id
    138 schema:value 9604648
    139 rdf:type schema:PropertyValue
    140 Nb18e1d513a0b498183700ce04736c4ce rdf:first sg:person.0717175012.11
    141 rdf:rest rdf:nil
    142 Nb2933f00237342f99992865a8e7d41b7 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    143 schema:name Biotechnology
    144 rdf:type schema:DefinedTerm
    145 Nc160b51024f744fe98179cd8b309cecc schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    146 schema:name Catalytic Domain
    147 rdf:type schema:DefinedTerm
    148 Nc8fa25d341e6494987e35abb55f14b94 schema:issueNumber 7
    149 rdf:type schema:PublicationIssue
    150 Nd2b0cb6648004811ba9aedd8ce3055c6 schema:volumeNumber 25
    151 rdf:type schema:PublicationVolume
    152 Ndc5d52220bfe4b2b8d47e1ba75704e04 rdf:first Nf8bdfbe4b6724eda8abc17896a88c06b
    153 rdf:rest Nf1b89d429b984aa0bae707d1ace3978a
    154 Ne47c6d0b44b64f8aaa7d31c1c35819f5 schema:affiliation https://www.grid.ac/institutes/grid.14095.39
    155 schema:familyName Szczepek
    156 schema:givenName Michal
    157 rdf:type schema:Person
    158 Nf1b89d429b984aa0bae707d1ace3978a rdf:first sg:person.01044507752.93
    159 rdf:rest Nb18e1d513a0b498183700ce04736c4ce
    160 Nf49859cbd09e4b1092b8fc7cda40de35 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    161 schema:name Cell Line, Tumor
    162 rdf:type schema:DefinedTerm
    163 Nf8bdfbe4b6724eda8abc17896a88c06b schema:familyName Serrano
    164 schema:givenName Luis
    165 rdf:type schema:Person
    166 Nfccbed05c0934c62b4078aa988e1c60e schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    167 schema:name Sequence Homology, Amino Acid
    168 rdf:type schema:DefinedTerm
    169 Nfdaea91a92d8486eae20f37f2fe36cd1 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
    170 schema:name Zinc Fingers
    171 rdf:type schema:DefinedTerm
    172 anzsrc-for:06 schema:inDefinedTermSet anzsrc-for:
    173 schema:name Biological Sciences
    174 rdf:type schema:DefinedTerm
    175 anzsrc-for:0601 schema:inDefinedTermSet anzsrc-for:
    176 schema:name Biochemistry and Cell Biology
    177 rdf:type schema:DefinedTerm
    178 sg:grant.2603762 http://pending.schema.org/fundedItem sg:pub.10.1038/nbt1317
    179 rdf:type schema:MonetaryGrant
    180 sg:journal.1115214 schema:issn 1087-0156
    181 1546-1696
    182 schema:name Nature Biotechnology
    183 rdf:type schema:Periodical
    184 sg:person.01044507752.93 schema:familyName Segal
    185 schema:givenName David J
    186 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01044507752.93
    187 rdf:type schema:Person
    188 sg:person.01056624027.62 schema:familyName Brondani
    189 schema:givenName Vincent
    190 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01056624027.62
    191 rdf:type schema:Person
    192 sg:person.0704613520.44 schema:familyName Büchel
    193 schema:givenName Janine
    194 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0704613520.44
    195 rdf:type schema:Person
    196 sg:person.0717175012.11 schema:familyName Cathomen
    197 schema:givenName Toni
    198 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0717175012.11
    199 rdf:type schema:Person
    200 sg:pub.10.1038/40446 schema:sameAs https://app.dimensions.ai/details/publication/pub.1008028344
    201 https://doi.org/10.1038/40446
    202 rdf:type schema:CreativeWork
    203 sg:pub.10.1038/nature03556 schema:sameAs https://app.dimensions.ai/details/publication/pub.1040117781
    204 https://doi.org/10.1038/nature03556
    205 rdf:type schema:CreativeWork
    206 sg:pub.10.1038/nbt794 schema:sameAs https://app.dimensions.ai/details/publication/pub.1008187948
    207 https://doi.org/10.1038/nbt794
    208 rdf:type schema:CreativeWork
    209 sg:pub.10.1385/1-59745-116-9:207 schema:sameAs https://app.dimensions.ai/details/publication/pub.1037986294
    210 https://doi.org/10.1385/1-59745-116-9:207
    211 rdf:type schema:CreativeWork
    212 https://app.dimensions.ai/details/publication/pub.1075329244 schema:CreativeWork
    213 https://app.dimensions.ai/details/publication/pub.1077293533 schema:CreativeWork
    214 https://doi.org/10.1006/jmbi.1998.1747 schema:sameAs https://app.dimensions.ai/details/publication/pub.1007956468
    215 rdf:type schema:CreativeWork
    216 https://doi.org/10.1016/j.jmb.2005.10.010 schema:sameAs https://app.dimensions.ai/details/publication/pub.1051974502
    217 rdf:type schema:CreativeWork
    218 https://doi.org/10.1016/j.jmb.2005.10.050 schema:sameAs https://app.dimensions.ai/details/publication/pub.1023503877
    219 rdf:type schema:CreativeWork
    220 https://doi.org/10.1016/j.jmb.2006.06.063 schema:sameAs https://app.dimensions.ai/details/publication/pub.1043647943
    221 rdf:type schema:CreativeWork
    222 https://doi.org/10.1016/j.ymthe.2005.06.094 schema:sameAs https://app.dimensions.ai/details/publication/pub.1023502951
    223 rdf:type schema:CreativeWork
    224 https://doi.org/10.1016/j.ymthe.2005.08.003 schema:sameAs https://app.dimensions.ai/details/publication/pub.1043579457
    225 rdf:type schema:CreativeWork
    226 https://doi.org/10.1016/s0022-2836(02)00442-4 schema:sameAs https://app.dimensions.ai/details/publication/pub.1013603912
    227 rdf:type schema:CreativeWork
    228 https://doi.org/10.1073/pnas.0501980102 schema:sameAs https://app.dimensions.ai/details/publication/pub.1035557908
    229 rdf:type schema:CreativeWork
    230 https://doi.org/10.1073/pnas.0506124102 schema:sameAs https://app.dimensions.ai/details/publication/pub.1031394506
    231 rdf:type schema:CreativeWork
    232 https://doi.org/10.1073/pnas.0510187103 schema:sameAs https://app.dimensions.ai/details/publication/pub.1011497430
    233 rdf:type schema:CreativeWork
    234 https://doi.org/10.1073/pnas.111009698 schema:sameAs https://app.dimensions.ai/details/publication/pub.1036799989
    235 rdf:type schema:CreativeWork
    236 https://doi.org/10.1073/pnas.2135381100 schema:sameAs https://app.dimensions.ai/details/publication/pub.1036939244
    237 rdf:type schema:CreativeWork
    238 https://doi.org/10.1073/pnas.93.3.1156 schema:sameAs https://app.dimensions.ai/details/publication/pub.1001210891
    239 rdf:type schema:CreativeWork
    240 https://doi.org/10.1073/pnas.95.18.10564 schema:sameAs https://app.dimensions.ai/details/publication/pub.1037239563
    241 rdf:type schema:CreativeWork
    242 https://doi.org/10.1073/pnas.95.18.10570 schema:sameAs https://app.dimensions.ai/details/publication/pub.1022863238
    243 rdf:type schema:CreativeWork
    244 https://doi.org/10.1073/pnas.96.6.2758 schema:sameAs https://app.dimensions.ai/details/publication/pub.1043463987
    245 rdf:type schema:CreativeWork
    246 https://doi.org/10.1074/jbc.272.45.28545 schema:sameAs https://app.dimensions.ai/details/publication/pub.1020122890
    247 rdf:type schema:CreativeWork
    248 https://doi.org/10.1074/jbc.273.10.5858 schema:sameAs https://app.dimensions.ai/details/publication/pub.1040536653
    249 rdf:type schema:CreativeWork
    250 https://doi.org/10.1074/jbc.m102604200 schema:sameAs https://app.dimensions.ai/details/publication/pub.1026702498
    251 rdf:type schema:CreativeWork
    252 https://doi.org/10.1074/jbc.m110669200 schema:sameAs https://app.dimensions.ai/details/publication/pub.1020428610
    253 rdf:type schema:CreativeWork
    254 https://doi.org/10.1074/jbc.m506654200 schema:sameAs https://app.dimensions.ai/details/publication/pub.1038367262
    255 rdf:type schema:CreativeWork
    256 https://doi.org/10.1083/jcb.146.5.905 schema:sameAs https://app.dimensions.ai/details/publication/pub.1001594320
    257 rdf:type schema:CreativeWork
    258 https://doi.org/10.1093/nar/23.24.5012 schema:sameAs https://app.dimensions.ai/details/publication/pub.1024116167
    259 rdf:type schema:CreativeWork
    260 https://doi.org/10.1093/nar/28.17.3361 schema:sameAs https://app.dimensions.ai/details/publication/pub.1051444401
    261 rdf:type schema:CreativeWork
    262 https://doi.org/10.1093/nar/gkg375 schema:sameAs https://app.dimensions.ai/details/publication/pub.1016134561
    263 rdf:type schema:CreativeWork
    264 https://doi.org/10.1093/nar/gkl076 schema:sameAs https://app.dimensions.ai/details/publication/pub.1001212823
    265 rdf:type schema:CreativeWork
    266 https://doi.org/10.1126/science.1078395 schema:sameAs https://app.dimensions.ai/details/publication/pub.1003888273
    267 rdf:type schema:CreativeWork
    268 https://doi.org/10.1126/science.1134833 schema:sameAs https://app.dimensions.ai/details/publication/pub.1044417952
    269 rdf:type schema:CreativeWork
    270 https://doi.org/10.1128/jvi.74.23.11407-11412.2000 schema:sameAs https://app.dimensions.ai/details/publication/pub.1041857462
    271 rdf:type schema:CreativeWork
    272 https://doi.org/10.1128/mcb.14.12.8096 schema:sameAs https://app.dimensions.ai/details/publication/pub.1022051171
    273 rdf:type schema:CreativeWork
    274 https://doi.org/10.1128/mcb.15.4.1968 schema:sameAs https://app.dimensions.ai/details/publication/pub.1034391289
    275 rdf:type schema:CreativeWork
    276 https://doi.org/10.1128/mcb.17.1.267 schema:sameAs https://app.dimensions.ai/details/publication/pub.1039424106
    277 rdf:type schema:CreativeWork
    278 https://doi.org/10.1128/mcb.21.1.289-297.2001 schema:sameAs https://app.dimensions.ai/details/publication/pub.1019605954
    279 rdf:type schema:CreativeWork
    280 https://doi.org/10.1128/mcb.23.10.3550-3557.2003 schema:sameAs https://app.dimensions.ai/details/publication/pub.1002760154
    281 rdf:type schema:CreativeWork
    282 https://doi.org/10.1128/mcb.23.10.3558-3565.2003 schema:sameAs https://app.dimensions.ai/details/publication/pub.1040854262
    283 rdf:type schema:CreativeWork
    284 https://doi.org/10.1534/genetics.105.052829 schema:sameAs https://app.dimensions.ai/details/publication/pub.1014430276
    285 rdf:type schema:CreativeWork
    286 https://doi.org/10.1667/rr3516.1 schema:sameAs https://app.dimensions.ai/details/publication/pub.1068196612
    287 rdf:type schema:CreativeWork
    288 https://www.grid.ac/institutes/grid.14095.39 schema:alternateName Freie Universität Berlin
    289 schema:name Charité Medical School, Institute of Virology (CBF), 12203 Berlin, Germany.
    290 rdf:type schema:Organization
     




    Preview window. Press ESC to close (or click here)


    ...