Reactive oxygen species are involved in nickel inhibition of DNA repair

Abstract

Nickel has been shown to inhibit DNA repair in a way that may play a role in its toxicity. Since nickel treatment increases cellular reactive oxygen species (ROS), we have investigated the involvement of ROS in nickel inhibition of DNA repair. Inhibition of glutathione synthesis or catalase activity increased the enhancing effect of nickel on the cytotoxicity of ultraviolet (UV) light. Inhibition of catalase and glutathione peroxidase activities also enhanced the retardation effect of nickel on the rejoining of DNA strand breaks accumulated by hydroxyurea plus cytosine-beta-D-arabinofuranoside in UV-irradiated cells. Since DNA polymerization and ligation are involved in the DNA-break rejoining, we have investigated the effect of ROS on these two steps in an extract of Chinese hamster ovary cells. Nickel inhibition of the incorporation of (3H)dTTP into the DNase I-activated calf thymus DNA was stronger than the ligation of poly(dA) x oligo(dT), whereas H2O2 was more potent in inhibiting DNA ligation than DNA polymerization. Nickel, in the presence of H2O2, exhibited a synergistic inhibition on both DNA polymerization and ligation and caused protein fragmentation. In addition, glutathione could completely recover the inhibition by nickel or H2O2 alone but only partially recover the inhibition by nickel plus H2O2. Therefore, nickel may bind to DNA-repair enzymes and generate oxygen-free radicals to cause protein degradation in situ. This irreversible damage to the proteins involved in DNA repair, replication, recombination, and transcription could be important for the toxic effects of nickel.

Heavy metals, islet function and diabetes development

“…Nickel has been shown to impair DNA repair-related enzymes through the production of ROS. 111,118 Other studies have also indicated that nickel increases DNA bases oxidation in vitro and lipidperoxidation in vivo. 111,112,119 Several studies have demonstrated that nickel possesses the ability to induce hyperglycemia.…”

Nickel(II) Affects Poly(ADP-ribose) Polymerase-Mediated DNA Repair in Normal and Cancer Cells

“…Nickel may bind to DNA repair en-zymes and generates oxygen-free radicals to cause protein degradation in situ (Lynn et al, 1997). On the other hand, a competition of toxic metals with essential ions appears to be an important mechanism of their genotoxicity (Asmuss et al, 2000;Bal et al, 2003).…”

Interactions by Carcinogenic Metal Compounds with DNA Repair Processes

“…Inhibition of catalase and glutathione peroxidase activities also enhanced the retardation effect of nickel on the rejoining of DNA strand breaks accumulated by hydroxyurea plus cytosine-beta-D-arabinofuranoside in UVirradiated cells. Lynn et al, (1997) showed that nickel, in the presence of H 2 O 2 , exhibited a synergistic inhibition on both DNA polymerization and ligation and caused protein fragmentation. In addition, glutathione could completely repair the inhibition by nickel or H 2 O 2 alone but only partially the inhibition by nickel when associated with H 2 O 2 .…”

“…The mechanisms of this action may include interactions with a specific structure containing zinc or the -SH groups of repair proteins. Because nickel compounds, such as NiS, Ni 3 S 2 , NiO (black and green), and soluble NiCl 2 , have been shown to be active inducers of reactive oxygen species (ROS) in Chinese hamster ovary cells, the involvement of reactive oxygen species has been implicated in the inhibition of DNA repair (Lynn, 1997). Inhibition of glutathione synthesis or catalase activity increased the enhancing effect of nickel on the cytotoxicity of ultraviolet light.…”