Disruption of the zinc finger domain: a common target that underlies many of the effects of lead.
The health risks associated with exposure to heavy metals such as lead (Pb) remain a major public health concern. The zinc finger is a major structural motif involved in protein-nucleic acid interactions and is present in the largest superfamily of transcription factors. Zinc (Zn) ions coordinate this finger-like structure through bonds created with cysteine and histidine residues. Little information exists on the effects of heavy metals on proteins that contain structural repeats of this kind. Studies by us in the nervous system have shown that factors containing such motifs could be potential targets for perturbation by Pb. We have observed that metals such as Pb interfered with the DNA-binding properties of Sp1 and Egr-1, both in vivo and in vitro. Pb could also directly interfere with the DNA-binding of a recombinant human Sp1 protein. More recently, the effects of Pb on the DNA-binding of the zinc finger protein transcription factor IIIA (TFIIIA) have been demonstrated. Analysis on the effects of Pb on Sp1 revealed that alterations in its DNA-binding were commensurate with changes in the expression of its target genes. The action of Pb on Sp1, Egr-1, and TFIIIA suggests that it can also target other cellular proteins that contain the zinc finger motif and reveals this protein domain as a potential mediator for Pb-induced alterations in protein function. Thus by specifically targeting zinc finger proteins (ZFP), Pb is able to produce multiple responses through its action on a common site that is present in enzymes, channels and receptors.
Department of Biomedical Sciences, University of Rhode Island, Kingston 02881, USA. nzawia@uri.edu
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Zawia
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Crumpton
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Brydie
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Reddy
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Razmiafshari
D000818:Animals; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007854:Lead / Q000633:toxicity*; D014158:Transcription, Genetic / Q000187:drug effects; D016335:Zinc Fingers / Q000187:drug effects*
D007854:Lead; D004247:DNA