ArticleNucleic acids research2008
Computer design of obligate heterodimer meganucleases allows efficient cutting of custom DNA sequences.
Article in Nucleic acids research, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Using Gene Editing Approaches to Fine-Tune the Immune System.Frontiers in immunology · 2020Review
- Enhancing the specificity of recombinase-mediated genome engineering through dimer interface redesign.Journal of the American Chemical Society · 2014Article
- Reprogramming homing endonuclease specificity through computational design and directed evolution.Nucleic acids research · 2014Article
- Crystallization and preliminary crystallographic analysis of an Escherichia coli-selected mutant of the nuclease domain of the metallonuclease colicin E7.Acta crystallographica. Section F, Structural biology and crystallization communications · 2013Article
- Engineering domain fusion chimeras from I-OnuI family LAGLIDADG homing endonucleases.Nucleic acids research · 2012Article
- ZFN-site searches genomes for zinc finger nuclease target sites and off-target sites.BMC bioinformatics · 2011Article
- Successful targeting and disruption of an integrated reporter lentivirus using the engineered homing endonuclease Y2 I-AniI.PloS one · 2011Article
- Meganucleases and other tools for targeted genome engineering: perspectives and challenges for gene therapy.Current gene therapy · 2011Review
- Article
- Specificity in computational protein design.The Journal of biological chemistry · 2010Review
- Article
- Optimization algorithms for functional deimmunization of therapeutic proteins.BMC bioinformatics · 2010Article
- Homing endonucleases: from basics to therapeutic applications.Cellular and molecular life sciences : CMLS · 2010Review
- Efficient targeting of a SCID gene by an engineered single-chain homing endonuclease.Nucleic acids research · 2009Article
- Computational design of affinity and specificity at protein-protein interfaces.Current opinion in structural biology · 2009Review
- Rational engineering of type II restriction endonuclease DNA binding and cleavage specificity.Nucleic acids research · 2009Article
- Generation of single-chain LAGLIDADG homing endonucleases from native homodimeric precursor proteins.Nucleic acids research · 2009Article
- Crystal structure of I-DmoI in complex with its target DNA provides new insights into meganuclease engineering.Proceedings of the National Academy of Sciences of the United States of America · 2008Article
- Increasing cloning possibilities using artificial zinc finger nucleases.Proceedings of the National Academy of Sciences of the United States of America · 2008Article
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Authors and funding
5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Meganucleases cut long (>12 bp) unique sequences in genomes and can be used to induce targeted genome engineering by homologous recombination in the vicinity of their cleavage site. However, the use of natural meganucleases is limited by the repertoire of their target sequences, and considerable efforts have been made to engineer redesigned meganucleases cleaving chosen targets. Homodimeric meganucleases such as I-CreI have provided a scaffold, but can only be modified to recognize new quasi-palindromic DNA sequences, limiting their general applicability. Other groups have used dimer-interface redesign and peptide linkage to control heterodimerization between related meganucleases such as I-DmoI and I-CreI, but until now there has been no application of this aimed specifically at the scaffolds from existing combinatorial libraries of I-CreI. Here, we show that engineering meganucleases to form obligate heterodimers results in functional endonucleases that cut non-palindromic sequences. The protein design algorithm (FoldX v2.7) was used to design specific heterodimer interfaces between two meganuclease monomers, which were themselves engineered to recognize different DNA sequences. The new monomers favour functional heterodimer formation and prevent homodimer site recognition. This design massively increases the potential repertoire of DNA sequences that can be specifically targeted by designed I-CreI meganucleases and opens the way to safer targeted genome engineering.
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