Designer zinc-finger proteins and their applications.
The Cys(2)His(2) zinc finger is one of the most common DNA-binding motifs in Eukaryota. A simple mode of DNA recognition by the Cys(2)His(2) zinc finger domain provides an ideal scaffold for designing proteins with novel sequence specificities. The ability to bind specifically to virtually any DNA sequence combined with the potential of fusing them with effector domains has led to the technology of engineering of chimeric DNA-modifying enzymes and transcription factors. This in turn has opened the possibility of using the engineered zinc finger-based factors as novel human therapeutics. One such synthetic factor-designer zinc finger transcription activator of the vascular endothelial growth factor A gene-has recently entered clinical trials to evaluate the ability of stimulating the growth of blood vessels in treating the peripheral arterial obstructive disease. This review concentrates on the aspects of natural Cys(2)His(2) zinc fingers evolution and fundamental steps in design of engineered zinc finger proteins. The applications of engineered zinc finger proteins are discussed in a context of the mechanism mediating their effect on the targeted DNA. Furthermore, the regulation of the expression of zinc finger proteins and their targeting to various cellular compartments and to chromatin and non-chromatin target templates are described. Also possible future applications of designer zinc finger proteins are discussed.
Papworth
Monika
M
MRC Laboratory of Molecular Biology, Hills Road, CB2 2QH, UK. map@mrc-lmb.cam.ac.uk
Kolasinska
Paulina
P
Minczuk
Michal
M
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy; D019143:Evolution, Molecular; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects; D015202:Protein Engineering / Q000379:methods; D011993:Recombinant Fusion Proteins / Q000235:genetics* / Q000627:therapeutic use; D014157:Transcription Factors / Q000235:genetics* / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics; D016335:Zinc Fingers / Q000235:genetics*
D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A