ArticleJournal of the American Chemical Society2014
Enhancing the specificity of recombinase-mediated genome engineering through dimer interface redesign.
Article in Journal of the American Chemical Society, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 30 citations in OpenAlex.
- Advances in large-scale DNA engineering with the CRISPR system.Experimental & molecular medicine · 2025Review
- Expanding the DNA editing toolbox: Novel lambda integrase variants targeting microalgal and human genome sequences.PloS one · 2024Article
- Programmable deletion, replacement, integration and inversion of large DNA sequences with twin prime editing.Nature biotechnology · 2022Article
- Correction of a Factor VIII genomic inversion with designer-recombinases.Nature communications · 2022Article
- RNA-Guided Recombinase-Cas9 Fusion Targets Genomic DNA Deletion and Integration.The CRISPR journal · 2019Article
- Engineering altered protein-DNA recognition specificity.Nucleic acids research · 2018Review
- Beyond editing to writing large genomes.Nature reviews. Genetics · 2017Article
- Engineering and Application of Zinc Finger Proteins and TALEs for Biomedical Research.Molecules and cells · 2017Review
- Genome-Editing Technologies: Principles and Applications.Cold Spring Harbor perspectives in biology · 2016Review
- A programmable Cas9-serine recombinase fusion protein that operates on DNA sequences in mammalian cells.Nucleic acids research · 2016Article
- Article
- Formation of functional super-helical assemblies by constrained single heptad repeat.Nature communications · 2015Article
- Article
- Synthetic zinc finger proteins: the advent of targeted gene regulation and genome modification technologies.Accounts of chemical research · 2014Article
- Protein delivery using Cys2-His2 zinc-finger domains.ACS chemical biology · 2014Article
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Despite recent advances in genome engineering made possible by the emergence of site-specific endonucleases, there remains a need for tools capable of specifically delivering genetic payloads into the human genome. Hybrid recombinases based on activated catalytic domains derived from the resolvase/invertase family of serine recombinases fused to Cys2-His2 zinc-finger or TAL effector DNA-binding domains are a class of reagents capable of achieving this. The utility of these enzymes, however, has been constrained by their low overall targeting specificity, largely due to the formation of side-product homodimers capable of inducing off-target modifications. Here, we combine rational design and directed evolution to re-engineer the serine recombinase dimerization interface and generate a recombinase architecture that reduces formation of these undesirable homodimers by >500-fold. We show that these enhanced recombinases demonstrate substantially improved targeting specificity in mammalian cells and achieve rates of site-specific integration similar to those previously reported for site-specific nucleases. Additionally, we show that enhanced recombinases exhibit low toxicity and promote the delivery of the human coagulation factor IX and α-galactosidase genes into endogenous genomic loci with high specificity. These results provide a general means for improving hybrid recombinase specificity by protein engineering and illustrate the potential of these enzymes for basic research and therapeutic applications.
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Registered trials
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.