Interference by toxic metal compounds with isolated zinc finger DNA repair proteins (original) (raw)
Related papers
Carcinogenesis, 2000
environmental hazards. From epidemiological studies and/or animal experiments it is well known that compounds of and Andrea Hartwig 1, 4 chromium, arsenic, cadmium, nickel and cobalt are carcinocells in culture. Nevertheless, these metal compounds enhance Netherlands the genotoxic effects of different mutagens such as UVC radiation, X-rays, benzo[a]pyrene, cis-diamminedichloroplatinum(II) (cisplatin) or DNA alkylating agents (1) and inhibit DNA repair processes. Nucleotide excision repair (NER), Even though not mutagenic, compounds of the carcinogenic which is involved in the removal of DNA damage induced by metals nickel, cadmium, cobalt and arsenic have been a variety of environmental mutagens including UV light, shown previously to inhibit nucleotide excision repair and aromatic amines and polyaromatic hydrocarbons, is inhibited base excision repair at low, non-cytotoxic concentrations.
Chemical Research in Toxicology, 2004
XPA is one of the key members of the protein complex of the nucleotide excision repair (NER) pathway of DNA repair. The CCCC zinc finger domain of XPA is involved in the interactions with other NER proteins. To study the possible molecular mechanisms of XPA inhibition, we previously investigated Zn(II) and Ni(II) interactions with the synthetic 37 amino acid peptide (XPAzf), AcDYVICEECGKEFMDSYLMNHFDLPTCDNCRDADDKHKam, representing the XPA zinc finger sequence (Bal, W., Schwerdtle, T., and Hartwig, A. Mechanism of nickel assault on the zinc finger of DNA repair protein XPA. Chem. Res. Toxicol. 16,[242][243][244][245][246][247][248]. In this work, we extended these studies on other carcinogenic metal ions, Co(II) and Cd(II). The binding constants and complex geometries were determined using UV-vis and CD spectroscopies, and oxidative damage to XPAzf was studied with HPLC. The conditional binding constants determined for Co(II) and Cd(II) in 50 mM phosphate buffer, pH 7.4, are 10 7.4(0.4 and 10 12.8(0.5 , respectively, yielding binding constant ratios Zn(II)/Co(II) of 100 and Zn(II)/ Cd(II) of 0.001, which are the lowest values reported for zinc fingers so far. The Co(II) ion forms a tetrahedral complex with the sulfurs of XPAzf, which is isostructural with the native zinc finger. The Cd(II) complex is somewhat less structured. The oxidation of Zn(II)-saturated XPAzf by H 2 O 2 is accelerated in the presence of Co(II), but the concentration profile of this effect indicates the formation of an active Co(II) complex external to the metal-sulfur center. The Cd(II)-saturated XPAzf is very resistant to oxidation by H 2 O 2 . Overall, our results indicate that XPAzf can undergo Co(II) and Cd(II) assault under specific conditions.
Carcinogenesis, 1997
radical attack, has been observed after treatment of isolated 1 To whom correspondence should be addressed calf thymus DNA with nickel(II) and H 2 O 2 (6) and of isolated Compounds of nickel(II) and cadmium(II) are carcinogenic human chromatin with nickel(II) in the absence or presence to humans and to experimental animals. One frequently of H 2 O 2 (7). The formation of 7,8-dihydro-8-oxoguanine discussed mechanism involved in tumor formation is an (8-hydroxyguanine*) was further enhanced when nickel(II) increase in reactive oxygen species by both metals with the was complexed to heterochromatic proteins (8). An increase subsequent generation of oxidative DNA damage. In the in oxidative DNA damage by nickel(II) has also been detected present study we used human HeLa cells to investigate the in experimental animals. An elevated level of 8-hydroxypotential of nickel(II) and cadmium(II) to induce DNA guanine was induced in rat kidney cells after a single i.p. lesions typical for oxygen free radicals in intact cells and injection of nickel acetate (9), and the extent was considerably the effect on their repair. As indicators of oxidative DNA higher after the administration of nickel(II)-histidine (10). damage, we determined the frequencies of DNA strand Nevertheless, data supporting the induction of oxidative DNA breaks and of lesions recognized by the bacterial formdamage in mammalian cells in culture are still missing.
Modulation of DNA repair processes by arsenic and selenium compounds
Toxicology, 2003
Nickel, cadmium, cobalt and arsenic compounds are well known carcinogens to humans and experimental animals. In addition to the induction of mainly oxidative DNA damage, they interfere with nucleotide and base excision repair (BER) at low, non-cytotoxic concentrations. In case of arsenic, an inactivation of DNA repair has also been observed for the trivalent and pentavalent methylated metabolites, with the strongest effects exerted by MMA(III) and DMA(III). As potential molecular targets, interactions with so-called zinc finger proteins involved in DNA repair and/or DNA damage signaling have been identified. For example, arsenite suppresses poly(ADP-ribosyl)ation at extremely low, environmentally relevant concentrations. Also, Fpg and XPA involved in BER and NER, respectively, are inactivated by arsenite, MMA(III) and DMA(III). Nevertheless, an interaction with the zinc finger structures of DNA repair proteins may also occur by essential trace elements such as certain selenium compounds, which appear to exert anticarcinogenic properties at low concentrations but may compromise genetic stability at higher concentrations.
Role of DNA repair inhibition in lead- and cadmium-induced genotoxicity: a review
Environmental Health Perspectives, 1994
Compounds of lead and cadmium have been shown to be carcinogenic to humans and experimental animals. However, the underlying mechanisms are still not understood. In mammalian cells in culture, lead(lIl) is weakly mutagenic after long incubation times and generates DNA strand breaks only after treatment with high, toxic doses. Cadmium(ll) induces DNA strand breaks and chromosomal aberrations, but its mutagenic potential is rather weak. However, both metals exert pronounced indirect genotoxic effects. Lead(ll) is comutagenic towards UV and N-methyl-N-nitro-Nnitrosoguanidine (MNNG) and enhances the number of UV-induced sister chromatid exchanges in V79 Chinese hamster cells. With regard to DNA repair, lead(ll) causes an accumulation of DNA strand breaks after UV-irradiation in HeLa cells, indicating an interference with the polymerization or ligation step in excision repair. Cadmium(ll) enhances the mutagenicity of UV light in V79 Chinese hamster cells and an increased sensitivity toward UV light is observed in various rodent and human cell lines. Furthermore, an inhibition of unscheduled DNA synthesis after UV-irradiation and a partial inhibition of the removal of UV-induced DNA lesions has been shown. For both metals, the indirect genotoxic effects are observed at low, nontoxic concentrations, suggesting that an interference with DNA repair processes may be predominant at biologically relevant concentrations. This might also explain the conflicting results of epidemiological studies obtained for both metals. Possible mechanisms of repair inhibiton are discussed.
Arsenic co-carcinogenesis: Inhibition of DNA repair and interaction with zinc finger proteins
Seminars in Cancer Biology, 2021
Arsenic is widely present in the environment and is associated with various population health risks including cancers. Arsenic exposure at environmentally relevant levels enhances the mutagenic effect of other carcinogens such as ultraviolet radiation. Investigation on the molecular mechanisms could inform the prevention and intervention strategies of arsenic carcinogenesis and co-carcinogenesis. Arsenic inhibition of DNA repair has been demonstrated to be an important mechanism, and certain DNA repair proteins have been identified to be extremely sensitive to arsenic exposure. This review will summarize the recent advances in understanding the mechanisms of arsenic carcinogenesis and co-carcinogenesis, including DNA damage induction and ROS generation, particularly how arsenic inhibits DNA repair through an integrated molecular mechanism which includes its interactions with sensitive zinc finger DNA repair proteins.
2010
The well established toxicity of cadmium and cadmium compounds results from their additive effects on several key cellular processes, including DNA repair. Mammalian cells have evolved several biochemical pathways to repair DNA lesions and maintain genomic integrity. By interfering with the homeostasis of redox metals and antioxidant systems, cadmium promotes the development of an intracellular environment that results in oxidative DNA damage which can be mutagenic if unrepaired. Small base lesions are recognised by specialized glycosylases and excised from the DNA molecule. The resulting abasic sites are incised, and the correct sequences restored by DNA polymerases using the opposite strands as template. Bulky lesions are recognised by a different set of proteins and excised from DNA as part of an oligonucleotide. As in base repair, the resulting gaps are filled by DNA polymerases using the opposite strands as template. Thus, these two repair pathways consist in excision of the lesion followed by DNA synthesis. In this study, we analysed in vitro the direct effects of cadmium exposure on the functionality of base and nucleotide DNA repair pathways. To this end, we used recently described dedicated microarrays that allow the parallel monitoring in cell extracts of the repair activities directed against several model base and/or nucleotide lesions. Both base and nucleotide excision/repair pathways are inhibited by CdCl 2 , with different sensitivities. The inhibitory effects of cadmium affect mainly the recognition and excision stages of these processes. Furthermore, our data indicate that the repair activities directed against different damaged bases also exhibit distinct sensitivities, and the direct comparison of cadmium effects on the excision of uracile in different sequences even allows us to propose a hierarchy of cadmium sensibility within the glycosylases removing U from DNA. These results indicate that, in our experimental conditions, cadmium is a very potent DNA repair poison.
DNA Damage by Heavy Metals in Animals and Human Beings: An Overview
Biochemistry & Pharmacology: Open Access
Cancer causing materials are found in air, water and in some other consumer products in the form of heavy metals. Biomedical research has shown that exposure to heavy metals is an important source of DNA damage in human beings and in animals. Heavy metals like iron, copper, chromium, lead, zinc, mercury, nickel etc. and reactive oxygen species enhance peroxidation of lipids and DNA damage. Elements like arsenic, nickel and cadmium are the ambassadors of mutagenic changes in cell. In mammalian cells it was found that DNA single strand breaks chromosomal aberrations occurred and sister chromatids exchange due to various nickel salts. It is now a wellestablished fact that cadmium causes cancer in tissues of animals. Exposure to cadmium develops cancer in prostate gland, kidney, liver and stomach. Through base pair mutation cancer causing metals damage DNA. However, some heavy metals directly damage the DNA thus generating negative results. The synthesis of nucleic acids and proteins is affected by cadmium. However, cadmium does not have a strong mutagenic nature when compared to other heavy metals. The present review aims to prospect the exposure (of human beings and animals) to heavy metals, cause of different diseases in both and mutagenic effect of heavy metals on double strand repair.
Direct DNA interaction and genotoxic impact of three metals: Cadmium, nickel and aluminum
The Journal of Chemical Thermodynamics, 2018
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