Summary
Compounds of nickel(II), cadmium(II), cobalt(II) and arsenic(III) have been shown previously to disturb DNA repair processes at low, non-cytotoxic concentrations. They inhibit nucleotide excision repair involved in the removal of a broad spectrum of DNA lesions induced by environmental mutagens as well as the repair of oxidative DNA damage generated endogenously due to oxygen metabolism. This raises the question why DNA repair systems are such sensitive intracellular targets of metal-induced toxicity. We found that different steps are affected and different mechanisms account for metal-induced repair inhibition. Nickel(II) and cadmium(II) interfere with the very first step of the repair process by disturbing DNA-protein interactions involved in DNA damage recognition. Since these effects are reversible by the addition of magnesium(II) and zinc(II), respectively, to nuclear extracts derived from metal-treated cells, the inactivations occur at the protein level and not at the level of gene expression and/or translation of the respective DNA repair proteins. Potentially very sensitive targets for toxic metal ions are zinc finger structures in DNA binding motifs, which have been identified in several DNA repair enzymes. They include the mammalian XPA protein essential for the recognition of DNA damage during nucleotide excision repair as well as the bacterial formamidopyrimidine-DNA glycosylase (Fpg protein) involved in the removal of oxidative DNA base modifications. By applying both proteins as models for zinc finger DNA repair proteins, we observed no inhibitory effect on the Fpg protein in the presence of up to 1 mM nickel(II) or cobalt(II); however, 10 μM nickel(II) disturbed XPA-DNA interactions on a cisplatin-damaged oligonucleotide. With respect to other metal compounds, 50 jiM cadmium(II), 5 μM copper(II) and 50 nM mercury(II) lead to pronounced inhibitions of the Fpg protein. The observed inhibitions were partly prevented by simultaneous treatment with zinc(II) in case of cadmium(II) and copper(IJ), but not mercury(II). Our results indicate that with respect to the Fpg protein, its zinc finger structure is a sensitive target for cadmium(II) and copper(II), but not for nickel(II) or mercury(II), providing further evidence that each metal exerts unique mechanisms of repair inhibition.
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Hartwig, A., Mullenders, L.H.F., Asmuß, M., Benters, M., Krüger, I. (1999). Effect of Metal Compounds on the Function of Zinc Finger Proteins Involved in DNA Repair. In: Sarkar, B. (eds) Metals and Genetics. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4723-5_11
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DOI: https://doi.org/10.1007/978-1-4615-4723-5_11
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