Interaction of selenium compounds with zinc finger proteins involved in DNA repair.
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 DNA-binding 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 sulfur-containing 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.
Blessing
Holger
H
Institute of Food Chemistry and Toxicology, University of Karlsruhe, Germany.
Kraus
Silke
S
Heindl
Philipp
P
Bal
Wojciech
W
Hartwig
Andrea
A
D000818:Animals; D004247:DNA / Q000378:metabolism; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D043382:DNA-Formamidopyrimidine Glycosylase / Q000737:chemistry / Q000378:metabolism*; D008668:Metallothionein / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D051381:Rats; D018036:Selenium Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013457:Sulfur Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051760:Xeroderma Pigmentosum Group A Protein; D015032:Zinc / Q000378:metabolism; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D018036:Selenium Compounds; D013457:Sulfur Compounds; D051760:Xeroderma Pigmentosum Group A Protein; D004247:DNA; D008668:Metallothionein; D043382:DNA-Formamidopyrimidine Glycosylase; D015032:Zinc