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 for the published observations that uranium exposure is associated with DNA repair deficiency in exposed human populations.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Cooper
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
authors.forename: Erica J
authors.initials: EJ
authors.lastname: Dashner
authors.affiliation: Department of Chemistry and Biochemistry, University of Montana, Missoula, MT 59812, USA.
authors.forename: Ranalda
authors.initials: R
authors.lastname: Tsosie
authors.affiliation: Department of Food and Nutrition, College of Human Ecology, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Young Mi
authors.initials: YM
authors.lastname: Cho
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA; Community Environmental Health Program, University of New Mexico Health Sciences Center College of Pharmacy, Albuquerque, NM 87131, USA.
authors.forename: Johnnye
authors.initials: J
authors.lastname: Lewis
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA. Electronic address: lhudson@salud.unm.edu.
authors.forename: Laurie G
authors.initials: LG
authors.lastname: Hudson
mesh_terms: D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004260:DNA Repair / Q000187:drug effects* / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000633:toxicity*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D014501:Uranium / Q000633:toxicity*
chemical_list: D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014501:Uranium; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
keywords: DNA damage; DNA repair; Poly(ADP-ribose) polymerase-1 (PARP-1); Uranium; Zinc finger