Published online 26 October 2005
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Zinc finger nucleases: custom-designed molecular scissors for genome engineering of plant and mammalian cells
1Department of Environmental Health Sciences, The Johns Hopkins University Bloomberg School of Public Health 615 North Wolfe Street, Baltimore, MD 21205-2179, USA 2Pondicherry Biotech Private Ltd. 21 Louis Pragasam Street, Pondicherry 605001, India 3Center for Bioinformatics, School of Life Sciences, Pondicherry University Pondicherry 605014, India 4Department of Pediatrics, University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard, Dallas, TX 75390, USA 5Department of Biochemistry, University of Texas Southwestern Medical Center 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
*To whom correspondence should be addressed. Tel: 410 614 2289; Fax: 410 955 0299; Email: schandra{at}jhsph.edu
Received August 2, 2005. Revised September 22, 2005. Accepted October 3, 2005.
Custom-designed zinc finger nucleases (ZFNs), proteins designed to cut at specific DNA sequences, are becoming powerful tools in gene targeting—the process of replacing a gene within a genome by homologous recombination (HR). ZFNs that combine the non-specific cleavage domain (N) of FokI endonuclease with zinc finger proteins (ZFPs) offer a general way to deliver a site-specific double-strand break (DSB) to the genome. The development of ZFN-mediated gene targeting provides molecular biologists with the ability to site-specifically and permanently modify plant and mammalian genomes including the human genome via homology-directed repair of a targeted genomic DSB. The creation of designer ZFNs that cleave DNA at a pre-determined site depends on the reliable creation of ZFPs that can specifically recognize the chosen target site within a genome. The (Cys2His2) ZFPs offer the best framework for developing custom ZFN molecules with new sequence-specificities. Here, we explore the different approaches for generating the desired custom ZFNs with high sequence-specificity and affinity. We also discuss the potential of ZFN-mediated gene targeting for ‘directed mutagenesis’ and targeted ‘gene editing’ of the plant and mammalian genome as well as the potential of ZFN-based strategies as a form of gene therapy for human therapeutics in the future.
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