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Interference by toxic metal ions with DNA repair processes and cell cycle control: molecular mechanisms
A Hartwig1, M Asmuss, I Ehleben
1Institut für Lebensmittelchemie und Toxikologie, Universität Karlsruhe, Postfach 6980, D-76128 Karlsruhe, Germany. andrea.hartwig@chemie.uni-karlsruhe.de
Abstract:
Nickel, cadmium, cobalt, and arsenic compounds are well-known carcinogens to humans and experimental animals. Even though their DNA-damaging potentials are rather weak, they interfere with the nucleotide and base excision repair at low, noncytotoxic concentrations. For example, both water-soluble Ni(II) and particulate black NiO greatly reduced the repair of DNA adducts induced by benzo[a]pyrene, an important environmental pollutant. Furthermore, Ni(II), As(III), and Co(II) interfered with cell cycle progression and cell cycle control in response to ultraviolet C radiation. As potential molecular targets, interactions with so-called zinc finger proteins involved in DNA repair and/or DNA damage signaling were investigated. We observed an inactivation of the bacterial formamidopyrimidine-DNA glycosylase (Fpg), the mammalian xeroderma pigmentosum group A protein (XPA), and the poly(adenosine diphosphate-ribose)polymerase (PARP). Although all proteins were inhibited by Cd(II) and Cu(II), XPA and PARP but not Fpg were inhibited by Co(II) and Ni(II). As(III) deserves special attention, as it inactivated only PARP, but did so at very low concentrations starting from 10 nM. Because DNA is permanently damaged by endogenous and environmental factors, functioning processing of DNA lesions is an important prerequisite for maintaining genomic integrity; its inactivation by metal compounds may therefore constitute an important mechanism of metal-related carcinogenicity.
Insights
Certain metal compounds, like nickel and arsenic, are carcinogens that disrupt DNA repair mechanisms. These metals can inactivate key proteins involved in DNA damage signaling and repair, potentially explaining their cancer-causing effects.
Area of Science:
- Environmental toxicology
- Molecular toxicology
- Carcinogenesis research
Background:
- Nickel, cadmium, cobalt, and arsenic compounds are recognized human carcinogens.
- These metals exhibit weak direct DNA-damaging potential but interfere with critical DNA repair pathways at non-cytotoxic levels.
Purpose of the Study:
- To investigate the mechanism by which metal compounds contribute to carcinogenicity.
- To identify molecular targets of metal-induced DNA repair interference, focusing on proteins involved in DNA repair and damage signaling.
Main Methods:
- Assessed the impact of metal compounds (Ni(II), Cd(II), Co(II), As(III), Cu(II)) on DNA repair processes, including nucleotide and base excision repair.
- Investigated the effects of metals on cell cycle progression following DNA damage (UV-C radiation).
- Examined the inactivation of specific DNA repair proteins: bacterial formamidopyrimidine-DNA glycosylase (Fpg), mammalian xeroderma pigmentosum group A protein (XPA), and poly(adenosine diphosphate-ribose)polymerase (PARP).
Main Results:
- Nickel and cadmium compounds inhibited DNA adduct repair induced by benzo[a]pyrene.
- Ni(II), As(III), and Co(II) disrupted cell cycle control in response to UV-C radiation.
- Metal ions inactivated Fpg, XPA, and PARP proteins; As(III) showed potent inactivation of PARP at nanomolar concentrations.
Conclusions:
- Metal compounds interfere with essential DNA repair and cell cycle control mechanisms.
- Inactivation of DNA repair proteins like PARP by metals such as arsenic may be a key mechanism underlying metal-induced carcinogenicity.
- Understanding these interactions is crucial for assessing the carcinogenic risk of environmental pollutants.