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.

Elevated autoimmunity in residents living near abandoned uranium mine sites on the Navajo Nation

“…Proximity to abandoned uranium mines also strongly predicted capacity of serum to induce inflammatory biomarkers in cultured endothelial cells [5], consistent with elevated oxidized low-density lipoprotein and other biomarkers of cardiovascular disease in this population [6]. Of possible mechanistic relevance, uranium at 10 μM inhibited poly(ADP-ribose)polymerase-1 and DNA repair in tissue culture cells [7].…”

Uranyl acetate induced DNA single strand breaks and AP sites in Chinese hamster ovary cells

“…Interestingly, the proposed uranium binding position of the N3 position of adenine in the minor groove has been shown to a binding site for d -block divalent metals Cu(II), Zn(II), and Cd(II) (Nielsen 1992). Although the specific mechanisms are unclear, current studies have shown that uranium induced cytotoxicity is significantly decreased with pre-treatments of zinc (Hao 2014, Cooper 2016). Further studies should not only focus on the formation of U-DNA adducts, but to determine if the adducts are responsible for the observed increased SSBs.…”

Inhibitory effect of uranyl nitrate on DNA double-strand break repair by depression of a set of proteins in the homologous recombination pathway

“…Previous reports suggested that some zinc finger-containing DNA repair proteins such as C2H2 zinc finger proteins Sp1, Aart and XPA could be inhibited by uranium. 36,37 Furthermore, the uranyl ion inhibited the activity of DNA repair protein PARP-1 and resulted in zinc loss from the protein. 37 This inhibition could be attributed to the direct binding action of uranyl ion to the zinc finger motif, which disturbs the activity of the protein or enzyme.…”

“…36,37 Furthermore, the uranyl ion inhibited the activity of DNA repair protein PARP-1 and resulted in zinc loss from the protein. 37 This inhibition could be attributed to the direct binding action of uranyl ion to the zinc finger motif, which disturbs the activity of the protein or enzyme. However, no evidence was found to support that uranium might also inhibit non-zinc finger DNA-binding proteins.…”