Interaction of selenium compounds with zinc finger proteins involved in DNA repair

Abstract

As an essential element, selenium is present in enzymes from several families, including glutathione peroxidases, and is thought to exert anticarcinogenic properties. A remarkable feature of selenium consists of its ability to oxidize thiols under reducing conditions. Thus, one mode of action recently suggested is the oxidation of thiol groups of metallothionein, thereby providing zinc for essential reactions. However, tetrahedral zinc ion complexation to four thiolates, similar to that found in metallothionein, is present in one of the major classes of transcription factors and other so-called zinc finger proteins. Within this study we investigated the effect of selenium compounds on the activity of the formamidopyrimidine-DNA glycosylase (Fpg), a zinc finger protein involved in base excision repair, and on the DNAbinding capacity and integrity of xeroderma pigmentosum group A protein (XPA), a zinc finger protein essential for nucleotide excision repair. The reducible selenium compounds phenylseleninic acid, phenylselenyl chloride, selenocystine, ebselen, and 2-nitrophenylselenocyanate caused a concentration-dependent decrease of Fpg activity, while no inhibition was detected with fully reduced selenomethionine, methylselenocysteine or some sulfurcontaining analogs. Furthermore, reducible selenium compounds interfered with XPA-DNA binding and released zinc from the zinc finger motif, XPAzf. Zinc release was even evident at high glutathione/oxidised glutathine ratios prevailing under cellular conditions. Finally, comparative studies with metallothionein and XPAzf revealed similar or even accelerated zinc release from XPAzf. Altogether, the results indicate that zinc finger motifs are highly reactive towards oxidizing selenium compounds. This could affect gene expression, DNA repair and, thus, genomic stability.

Interindividual Variability in Response to Sodium Dichromate–Induced Oxidative DNA Damage: Role of the Ser326Cys Polymorphism in the DNA-Repair Protein of 8-Oxo-7,8-Dihydro-2′-Deoxyguanosine DNA Glycosylase 1

“…We recognize that further analyses in a larger population and a wider range of antioxidant capacities are required for confirmation of our findings. In support of our observations a similar correlation between 8-oxo-dG in leukocytes and OGG1 genotype has been made by Tarng et al (79) (80) has reported that activity of the DNA repair protein XPA is modulated by redox modification to a zinc finger motif present in its active site. In addition, reduced repair capacity of variant OGG1 protein only under conditions of oxidative stress would explain why no difference between background levels of oxidative DNA damage was observed between the three groups.…”

Redox Regulation of DNA Repair: Implications for Human Health and Cancer Therapeutic Development

“…Se-induced activation of p53 is also dependent on the BRCA1 protein in recombinational repair, which is frequently mutated in familial breast cancer (55). It also was reported that Se inhibited DNA-binding activity of transcription factors such as AP-1, NF-kB, SP-1, and SP-3, as well as the DNA-repair proteins XPA in the NER pathway and formamidopyrimidine DNA glycosylase (FPG) in the BER pathway (27,76,131,195). These data imply that Se may reduce cancer incidence through modulating DNA repair, redox status of cells, and the cellular transcriptional response to oxidative stress.…”

Effect of short-term zinc supplementation on zinc and selenium tissue distribution and serum antioxidant enzymes

“…Such a fact indicates a signifi cant association between Zn and Se homeostasis. Moreover, a number of fundamental studies have investigated a chemical basis of this association (Blessing et al, 2004;Feroci et al, 2005). Earlier studies have indicated the possibility of mutual infl uence of zinc and selenium in the case of supplementation.…”