Zinc finger nucleases (ZFNs) are associated with cell death and apoptosis by binding at countless undesired locations. This\ncytotoxicity is associated with the binding ability of engineered zinc finger domains to bind dissimilar DNA sequences with high\naffinity. In general, binding preferences of transcription factors are associated with significant degenerated diversity and complexity\nwhich convolutes the design and engineering of preciseDNA binding domains. Evolutionary success of natural zinc finger proteins,\nhowever, evinces that nature created specific evolutionary traits and strategies, such as modularity and rank-specific recognition to\ncope with binding complexity that are critical for creating clinical viable tools to preciselymodify the human genome. Our findings\nindicate preservation of general modularity and significant alteration of the rank-specific binding preferences of the three-finger\nbinding domain of transcription factor SP1 when exchanging amino acids in the 2nd finger.
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