New insight into heavy metal toxicity as uranium is found to disrupt DNA transcription and repair proteins.

Wendy J. Hartsock, Jennifer D. Cohen, and David J. Segal*

Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721, and Genome Center and Department of Pharmacology, University of California, Davis, California 95616

Received December 4, 2006

Abstract:

Zinc finger proteins, one of the largest families of DNA-binding proteins in higher eukaryotes, are so named because they require zinc ions for appropriate structure and function. Dysregulation of zinc finger-containing DNA transcription and repair proteins has been proposed as a potential mechanism for the toxic effects of some metal ions. Uranium metal has been reported to be both a cytotoxic and a genotoxic agent. We hypothesized that these toxic effects of uranium might be due to its ability to directly disrupt zinc finger activity.

To test this hypothesis, two purified zinc finger proteins, Aart and Sp1, were analyzed by electrophoretic mobility shift in the presence of uranyl acetate. Inhibition of binding was apparent at 10 M uranyl acetate, while no inhibition was observed with up to 2000 M the cytotoxic metalloid sodium arsenite. Preincubation of the DNA with uranyl acetate did not inhibit zinc finger protein binding, suggesting that the inhibition was due to direct uranyl interaction with the protein. Surprisingly, uranyl acetate inhibited two nonzinc finger DNA-binding proteins, AP1 and NF-B, to a similar extent, and zinc finger inhibition was reduced in the presence of bovine serum albumin.

These results suggest that uranium can directly inhibit the function of DNA-binding proteins, most likely via a nonspecific protein interaction.

http://pubs.acs.org/cgi-bin/abstract.cgi/crtoec/2007/20/i05/abs/tx600347k.html