Artificial zinc finger peptides: creation, DNA recognition, and gene regulation

Proteins control most biological reactions and the disorder of their expres sion level causes many diseases. The advent of genomic sequencing and the a vailability of the complete sequences of several genomes provide new opport unities to study biology and to develop therapeutic strategies through spec ific modulation of the transcription of target genes. Therefore, regulation of the transcription level by "artificial repressors" is of special import ance. Of the DNA-binding motifs that have been manipulated by design or sel ection, Cys(2)-His(2) zinc finger proteins have demonstrated the greatest p otential for manipulation into general and specific transcription factors. Of special interest is the feature that this family of proteins has modular structures and can recognize a diverse set of DNA sequences in a sequence- specific manner. Therefore, zinc finger motifs offer an attractive framewor k for the design of novel DNA binding proteins, and such a DNA binding prot ein would be expected to possess a unique binding sequence with high specif icity and affinity. Principally, two approaches have been taken to the desi gn of artificial zinc finger proteins. One is a selection strategy via phag e display methods to alter the recognition sequence, and another is a struc ture-based linking strategy to extend the length of a DNA recognition seque nce. Such novel zinc finger peptides (or proteins) offer great promise for genome-specific transcription switches in the near future. (C) 2000 Elsevie r Science B.V. All rights reserved.