Zinc Finger-DNA Interaction: Effect of Metal Replacement, Free Radical Generation and DNA Damage and its Relevance to Carcinogenesis
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Zinc is abundantly present within the cell. Besides being in the active sites of many enzymes, zinc also acts as a structural component of many proteins. Zinc fingers belong to the latter class of proteins and form the largest known class of DNA-binding proteins. The steroid hormone receptor superfamily is a group of cytoplasmic receptors which act as transcriptional enhancer proteins. These receptors are zinc finger proteins and they bind specifically to short DNA sequences and control the transcription of a number of genes (1). Sequence comparisons revealed that a number of regions of varying degrees of conservation are shared by almost all the receptors (Fig. 1). The A/B domain, which is the most variable and differs considerably in size from one receptor to another is known to contain promoter- and cell-specific trans-activation function. The C domain is the most highly conserved of the regions and encodes the DNA binding domain. This region is connected to the region of next highest conservation, the E region, by the hinge or D region. The E region constitutes the hormone binding domain. It also contains transactivating and dimerization functions. The DNA binding domain C of these receptors are highly related and similarly stabilized by two zinc atoms each coordinated to 4 cysteine residues. The two fingers present in the DNA binding domain are not equivalent. The first finger (P box) is responsible for sequence specific DNA recognition while the second finger (D box) is involved in protein-protein cooperative interaction in the dimerization process. The hexameric sequence of the consensus response elements, their directionality and spacing dictate their specificity for receptor binding.
KeywordsZinc Finger Cleavage Pattern Estrogen Response Element Thyroid Receptor Half Site
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