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Zinc Finger Nucleases: A Molecular tool for Targeted Genetic AlterationsBY: Dr. Kiran B. Gaikwad | Category: Genetics | Submitted: 2015-01-04 23:44:44
Article Summary: "Zinc Finger Nucleases (ZFNs) can effectively and precisely manipulate the genome of plant, animal and insect species. These modifications have resulted in understanding of gene function, gene integration, gene disruption, mutagenesis and in treatment of various diseases or disorders including HIV.."
Every protein molecule has particular structure; likewise zinc finger is also a small protein structural motif, characterized by one or more zinc ions. The coordination between these zinc ions provides stability to the folds. Zinc finger was first identified in African fog Xenopus laevis (Klug and Rhodes 1987). In routine, zinc fingers coordinate zinc ions with pairs of cysteine and histidine residue in amino acid chain. The most important application of zinc finger is development of zinc finger nucleases (ZFNs). ZFNs are artificially synthesized rare cutting restriction enzymes which are developed by fusing zinc finger DNA binding domain with a DNA cleavage domain most specifically a type II restriction enzyme Fok I.
DNA cleavage domain: in order to cleave a DNA, the cleavage domain must dimerize, means, it should have two identical structural subunits. Therefore, two ZFNs are required to target non palindromic DNA site. These two ZFNs monomers bind to DNA target sequence in reverse orientation.
DNA binding domain: DNA binding domain of each ZFN contains 3-4 individual fingers, each capable of recognizing 3-bp long sequence. Thus, a heterodimer ZFN, composed of two 9-bp-long DNA binding domains will recognize an approximately 24-bp target sequence (Weinthal et al 2010)
Applications: ZFNs can be used to induce double stranded breaks (DSBs) in specific DNA sequence. A desired homologous donor DNA segment then could be inserted in this break followed by homologous recombination, which leads to tagged gene replacement. On the other hand, the DSBs in former DNA segment could be joined by non-homologous end joining (NHED), which leads to targeted mutagenesis. Important applications of ZFNs are as follows.
Cleavage of non-specific target site: it leads to;
a. Double stranded breaks at several locations which could results in chromosome segment translocations and other structural abnormalities
b. Integration of desired DNA in non-specific site could results in altered protein production which could be toxic / lethal for the individual.
1. Kandavelou K; Chandrasegaran S (2008). "Plasmids for Gene Therapy". Plasmids: Current Research and Future Trends. Caister Academic Press
2. Klug A, Rhodes D (1987). "Zinc fingers: a novel protein fold for nucleic acid recognition". Cold Spring Harb. Symp. Quant. Biol. 52: 473-82
3. Mittelman, D; Moye, C; Morton, J; Sykoudis, K; Lin, Y; Carroll, D; Wilson, JH (2009-06-16). "Zinc-finger directed double-strand breaks within CAG repeat tracts promote repeat instability in human cells". Proceedings of the National Academy of Sciences of the United States of America 106 (24): 9607-12
4. Weinthal, D., Tovkach, A., Zeevi, V., & Tzfira, T. (2010). Genome editing in plant cells by zinc finger nucleases. Trends in plant science, 15(6), 308-321.
About Author / Additional Info:
Scientist at Division of Genetics, Indian Agricultural research Institute. Presently doing research on identifying QTLs for genotype x management interaction for resource use efficiency in wheat.
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