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Title: Inhibition of poly(ADP-ribose)polymerase-1 and DNA repair by uranium

Abstract

Uranium has radiological and non-radiological effects within biological systems and there is increasing evidence for genotoxic and carcinogenic properties attributable to uranium through its heavy metal properties. In this study, we report that low concentrations of uranium (as uranyl acetate; < 10 μM) is not cytotoxic to human embryonic kidney cells or normal human keratinocytes; however, uranium exacerbates DNA damage and cytotoxicity induced by hydrogen peroxide, suggesting that uranium may inhibit DNA repair processes. Concentrations of uranyl acetate in the low micromolar range inhibited the zinc finger DNA repair protein poly(ADP-ribose) polymerase (PARP)-1 and caused zinc loss from PARP-1 protein. Uranyl acetate exposure also led to zinc loss from the zinc finger DNA repair proteins Xeroderma Pigmentosum, Complementation Group A (XPA) and aprataxin (APTX). In keeping with the observed inhibition of zinc finger function of DNA repair proteins, exposure to uranyl acetate enhanced retention of induced DNA damage. Co-incubation of uranyl acetate with zinc largely overcame the impact of uranium on PARP-1 activity and DNA damage. These findings present evidence that low concentrations of uranium can inhibit DNA repair through disruption of zinc finger domains of specific target DNA repair proteins. This may provide a mechanistic basis to account formore » the published observations that uranium exposure is associated with DNA repair deficiency in exposed human populations. - Highlights: • Low micromolar concentration of uranium inhibits polymerase-1 (PARP-1) activity. • Uranium causes zinc loss from multiple DNA repair proteins. • Uranium enhances retention of DNA damage caused by ultraviolet radiation. • Zinc reverses the effects of uranium on PARP activity and DNA damage repair.« less

Authors:
;  [1];  [2];  [3];  [1]
  1. Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131 (United States)
  2. Department of Chemistry and Biochemistry, University of Montana, Missoula, MT 59812 (United States)
  3. Department of Food and Nutrition, College of Human Ecology, Hanyang University, Seoul 133-791 (Korea, Republic of)
Publication Date:
OSTI Identifier:
22687876
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 291; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ACETATES; ADP; CONCENTRATION RATIO; CONGENITAL DISEASES; CYSTEINE; DNA; DNA DAMAGES; DNA REPAIR; HEREDITARY DISEASES; HISTIDINE; HISTONES; ICP MASS SPECTROSCOPY; KIDNEYS; PYRIMIDINE DIMERS; PYRIMIDINES; RIBOSE; URANIUM

Citation Formats

Cooper, Karen L., Dashner, Erica J., Tsosie, Ranalda, Cho, Young Mi, Lewis, Johnnye, Community Environmental Health Program, University of New Mexico Health Sciences Center College of Pharmacy, Albuquerque, NM 87131, and Hudson, Laurie G., E-mail: lhudson@salud.unm.edu. Inhibition of poly(ADP-ribose)polymerase-1 and DNA repair by uranium. United States: N. p., 2016. Web. doi:10.1016/J.TAAP.2015.11.017.
Cooper, Karen L., Dashner, Erica J., Tsosie, Ranalda, Cho, Young Mi, Lewis, Johnnye, Community Environmental Health Program, University of New Mexico Health Sciences Center College of Pharmacy, Albuquerque, NM 87131, & Hudson, Laurie G., E-mail: lhudson@salud.unm.edu. Inhibition of poly(ADP-ribose)polymerase-1 and DNA repair by uranium. United States. doi:10.1016/J.TAAP.2015.11.017.
Cooper, Karen L., Dashner, Erica J., Tsosie, Ranalda, Cho, Young Mi, Lewis, Johnnye, Community Environmental Health Program, University of New Mexico Health Sciences Center College of Pharmacy, Albuquerque, NM 87131, and Hudson, Laurie G., E-mail: lhudson@salud.unm.edu. Fri . "Inhibition of poly(ADP-ribose)polymerase-1 and DNA repair by uranium". United States. doi:10.1016/J.TAAP.2015.11.017.
@article{osti_22687876,
title = {Inhibition of poly(ADP-ribose)polymerase-1 and DNA repair by uranium},
author = {Cooper, Karen L. and Dashner, Erica J. and Tsosie, Ranalda and Cho, Young Mi and Lewis, Johnnye and Community Environmental Health Program, University of New Mexico Health Sciences Center College of Pharmacy, Albuquerque, NM 87131 and Hudson, Laurie G., E-mail: lhudson@salud.unm.edu},
abstractNote = {Uranium has radiological and non-radiological effects within biological systems and there is increasing evidence for genotoxic and carcinogenic properties attributable to uranium through its heavy metal properties. In this study, we report that low concentrations of uranium (as uranyl acetate; < 10 μM) is not cytotoxic to human embryonic kidney cells or normal human keratinocytes; however, uranium exacerbates DNA damage and cytotoxicity induced by hydrogen peroxide, suggesting that uranium may inhibit DNA repair processes. Concentrations of uranyl acetate in the low micromolar range inhibited the zinc finger DNA repair protein poly(ADP-ribose) polymerase (PARP)-1 and caused zinc loss from PARP-1 protein. Uranyl acetate exposure also led to zinc loss from the zinc finger DNA repair proteins Xeroderma Pigmentosum, Complementation Group A (XPA) and aprataxin (APTX). In keeping with the observed inhibition of zinc finger function of DNA repair proteins, exposure to uranyl acetate enhanced retention of induced DNA damage. Co-incubation of uranyl acetate with zinc largely overcame the impact of uranium on PARP-1 activity and DNA damage. These findings present evidence that low concentrations of uranium can inhibit DNA repair through disruption of zinc finger domains of specific target DNA repair proteins. This may provide a mechanistic basis to account for the published observations that uranium exposure is associated with DNA repair deficiency in exposed human populations. - Highlights: • Low micromolar concentration of uranium inhibits polymerase-1 (PARP-1) activity. • Uranium causes zinc loss from multiple DNA repair proteins. • Uranium enhances retention of DNA damage caused by ultraviolet radiation. • Zinc reverses the effects of uranium on PARP activity and DNA damage repair.},
doi = {10.1016/J.TAAP.2015.11.017},
journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = ,
volume = 291,
place = {United States},
year = {2016},
month = {1}
}