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Analysis of heat-labile sites generated by reactions of depleted uranium and ascorbate in plasmid DNA

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Abstract

The goal of this study was to characterize how depleted uranium (DU) causes DNA damage. Procedures were developed to assess the ability of organic and inorganic DNA adducts to convert to single-strand breaks (SSB) in pBR322 plasmid DNA in the presence of heat or piperidine. DNA adducts formed by methyl methanesulfonate, cisplatin, and chromic chloride were compared with those formed by reaction of uranyl acetate and ascorbate. Uranyl ion in the presence of ascorbate produced U–DNA adducts that converted to SSB on heating. Piperidine, which acted on DNA methylated by methyl methanesulfonate to convert methyl–DNA adducts to SSB, served in the opposite fashion as U–DNA adducts by decreasing the level of SSB. The observation that piperidine also decreased the gel shift for metal–DNA adducts formed by monofunctional cisplatin and chromic chloride was interpreted to suggest that piperidine served to remove U–DNA adducts. Radical scavengers did not affect the formation of uranium-induced SSB, suggesting that SSB arose from the presence of U–DNA adducts and not from the presence of free radicals. A model is proposed to predict how U–DNA adducts may serve as initial lesions that convert to SSB or AP sites. The results suggest that DU can act as a chemical genotoxin that does not require radiation for its mode of action. Characterizing the DNA lesions formed by DU is necessary to assess the relative importance of different DNA lesions in the formation of DU-induced mutations. Understanding the mechanisms of formation of DU-induced mutations may contribute to identification of biomarkers of DU exposure in humans.

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Abbreviations

ACES:

N-(2-Acetamido)-2-aminoethanesulfonic acid

Asc:

Ascorbate

CHO:

Chinese hamster ovary

DU:

Depleted uranium

MMS:

Methyl methanesulfonate

N7-MeG:

N 7-Methylguanine

UA:

Uranyl acetate

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Acknowledgments

This work was supported by NIH grant R15 ES019703. J.W. was supported by the STEP program within the Partnership for Native American Cancer Prevention (NIH grant U54 CA143925), and the John & Sophie Ottens Native American Student Research Program. A.Y. was supported by the Northern Arizona University Bridges Program (NIH grant R25 GM102788).

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Authors and Affiliations

  1. Department of Chemistry and Biochemistry, Northern Arizona University, PO Box 5698, Flagstaff, AZ, 86011-5698, USA

    Janice Wilson, Ashley Young, Edgar R. Civitello & Diane M. Stearns

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  1. Janice Wilson
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  2. Ashley Young
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  3. Edgar R. Civitello
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  4. Diane M. Stearns
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Correspondence to Diane M. Stearns.

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Wilson, J., Young, A., Civitello, E.R. et al. Analysis of heat-labile sites generated by reactions of depleted uranium and ascorbate in plasmid DNA. J Biol Inorg Chem 19, 45–57 (2014). https://doi.org/10.1007/s00775-013-1057-6

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  • DOI: https://doi.org/10.1007/s00775-013-1057-6

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