ArticleNucleic acids research2011
Molecular basis of engineered meganuclease targeting of the endogenous human RAG1 locus.
Article in Nucleic acids research, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 66 citations in OpenAlex.
- Genome editing via non-viral delivery platforms: current progress in personalized cancer therapy.Molecular cancer · 2022Review
- I-SceI and customized meganucleases-mediated genome editing in tomato and oilseed rape.Transgenic research · 2022Article
- Comparison of the Feasibility, Efficiency, and Safety of Genome Editing Technologies.International journal of molecular sciences · 2021Review
- Cell and Gene Therapy for Anemia: Hematopoietic Stem Cells and Gene Editing.International journal of molecular sciences · 2021Review
- Induced Pluripotent Stem Cell Meets Severe Combined Immunodeficiency.Cell journal · 2020Review
- Engineering altered protein-DNA recognition specificity.Nucleic acids research · 2018Review
- Beyond editing to writing large genomes.Nature reviews. Genetics · 2017Article
- Structure and dynamics of mesophilic variants from the homing endonuclease I-DmoI.Journal of computer-aided molecular design · 2017Article
- Applications of Alternative Nucleases in the Age of CRISPR/Cas9.International journal of molecular sciences · 2017Review
- Crystallographic analyses illustrate significant plasticity and efficient recoding of meganuclease target specificity.Nucleic acids research · 2017Article
- In vivo disruption of latent HSV by designer endonuclease therapy.JCI insight · 2016Article
- Build to understand: synthetic approaches to biology.Integrative biology : quantitative biosciences from nano to macro · 2016Review
- Venturing into the New Science of Nucleases.The Journal of investigative dermatology · 2016Article
- Mechanisms of gene targeting in higher eukaryotes.Cellular and molecular life sciences : CMLS · 2016Review
- Crystal Structure of the Homing Endonuclease I-CvuI Provides a New Template for Genome Modification.The Journal of biological chemistry · 2015Article
- Engineering a Nickase on the Homing Endonuclease I-DmoI Scaffold.The Journal of biological chemistry · 2015Article
- Genome-wide detection of DNA double-stranded breaks induced by engineered nucleases.Nature biotechnology · 2015Article
- Visualizing phosphodiester-bond hydrolysis by an endonuclease.Nature structural & molecular biology · 2015Article
- BuD, a helix-loop-helix DNA-binding domain for genome modification.Acta crystallographica. Section D, Biological crystallography · 2014Article
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Corrections and comments
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Authors and funding
21 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Homing endonucleases recognize long target DNA sequences generating an accurate double-strand break that promotes gene targeting through homologous recombination. We have modified the homodimeric I-CreI endonuclease through protein engineering to target a specific DNA sequence within the human RAG1 gene. Mutations in RAG1 produce severe combined immunodeficiency (SCID), a monogenic disease leading to defective immune response in the individuals, leaving them vulnerable to infectious diseases. The structures of two engineered heterodimeric variants and one single-chain variant of I-CreI, in complex with a 24-bp oligonucleotide of the human RAG1 gene sequence, show how the DNA binding is achieved through interactions in the major groove. In addition, the introduction of the G19S mutation in the neighborhood of the catalytic site lowers the reaction energy barrier for DNA cleavage without compromising DNA recognition. Gene-targeting experiments in human cell lines show that the designed single-chain molecule preserves its in vivo activity with higher specificity, further enhanced by the G19S mutation. This is the first time that an engineered meganuclease variant targets the human RAG1 locus by stimulating homologous recombination in human cell lines up to 265 bp away from the cleavage site. Our analysis illustrates the key features for à la carte procedure in protein-DNA recognition design, opening new possibilities for SCID patients whose illness can be treated ex vivo.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.