Interference by toxic metal ions with DNA repair processes and cell cycle control: molecular mechanisms.
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.
Hartwig
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Institut für Lebensmittelchemie und Toxikologie, Universität Karlsruhe, Postfach 6980, D-76128 Karlsruhe, Germany. andrea.hartwig@chemie.uni-karlsruhe.de
Asmuss
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M
Ehleben
I
I
Herzer
U
U
Kostelac
D
D
Pelzer
A
A
Schwerdtle
T
T
Bürkle
A
A
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000494:pharmacology; D043382:DNA-Formamidopyrimidine Glycosylase; D006801:Humans; D019216:Metals, Heavy / Q000009:adverse effects*; D009699:N-Glycosyl Hydrolases / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000494:pharmacology; D051760:Xeroderma Pigmentosum Group A Protein; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D019216:Metals, Heavy; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; D011065:Poly(ADP-ribose) Polymerases; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase