Cadmium Down-regulates Human OGG1 through Suppression of Sp1 Activity

Abstract

Cadmium is a well known human and animal carcinogen and is a ubiquitous contaminant in the environment. Although the carcinogenic mechanism of cadmium is a multifactorial process, oxidative DNA damage is believed to be of prime importance. In particular, cadmium suppresses the capacity of cells to repair oxidative DNA damage. In this study, cadmium treatment led to a significant increase in ␥-ray-induced 8-oxoguanine (8-oxoG) formation. Western blotting and semiquantitative reverse transcription-PCR revealed that cadmium treatment caused a decrease in the expression level of human OGG1 (8-oxoguanine-DNA glycosylase-1; hOGG1) in human fibroblast GM00637 and HeLa S3 cells. In addition, the cadmium-mediated decrease in hOGG1 transcription was the result of decreased binding of the transcription factor Sp1 to the hOGG1 promoter. Finally, we show that an increase in the functional hOGG1 expression level could inhibit the cadmium-mediated increase in ␥-ray-induced 8-oxoG accumulation as well as in ␥-radiation-induced mutation frequency at the HPRT (hypoxanthine-guanine phosphoribosyltransferase) gene locus. These results suggest that cadmium attenuates removal of ␥-ray-induced 8-oxoG adducts, which in turn increases the mutation frequency, and that this effect might, at least in part, result from suppression of hOGG1 transcription via inactivation of Sp1 as a result of cadmium treatment.

Interactions by Carcinogenic Metal Compounds with DNA Repair Processes

“…of the main DNA glycosylase activity responsible for the initiation of the base excision repair of 8-oxoguanine, an abundant and mutagenic form of oxidized guanine. The study of Bravard et al (2010) confirms that part of the inhibitory effect of low dose cadmium on the cellular 8-oxoguanine DNA glycosylase activity can be attributed to an already described reduced hOGG1 transcription (Youn et al, 2005). This moderate inhibitory effect of cadmium on hOGG1 mRNA levels cannot explain the d r a m a t i c d e c r e a s e o b s e r v e d i n t h e l e v e l s a n d a c t i v i t y o f h O G G 1 p r o t e i n .…”

Redox Regulation of Human OGG1 Activity in Response to Cellular Oxidative Stress

“…Here we show that the oxidative stress induced by a short exposure of human cells to a toxic concentration of cadmium results in nearly complete but reversible inactivation of the 8-oxoG DNA glycosylase activity of hOGG1. Chronic exposure to low doses of cadmium lowers the cellular activity of OGG1 in animal models (36,37) or in human cells (47). In the former cases, the cadmium-induced reduction of OGG1 activity was paralleled by lower enzyme levels most likely resulting from inhibition of gene expression at the transcriptional level.…”

“…However, at present little is known concerning the effect of cadmium on the human OGG1 (hOGG1) protein activity. Only one study recently addressed this question, demonstrating that several hours' exposure of human cells to low cadmium doses reduced hOGG1 activity through a decrease in the hOGG1 gene expression at the transcriptional level (47). The present study aimed at establishing whether an acute exposure of human cells to a high cadmium concentration alters the 8-oxoG DNA glycosylase activity of hOGG1 and at clarifying the underlying mechanisms of Cd genotoxicity.…”

Fragmentation of the DNA Repair Enzyme, OGG1, in Mouse Nonparenchymal Liver Cells by Arsenic Compounds

“…On the other hand, another possible mechanism for the inhibition of OGG1 activity was suggested by other groups. Recently, Youn et al reported that the cadmium-mediated decrease in hOGG1 transcription was the result of decreased binding of the transcription factor Sp1 to the hOGG1 promoter (28). Whether the same mechanism also occurs in arsenic compound-treated cells or animals remains unknown.…”