Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8320585 | DNA Repair | 2015 | 16 Pages |
Abstract
Cadmium (Cd) is a carcinogenic and neurotoxic environmental pollutant. Among the proposed mechanisms for Cd toxic effects, its ability to promote oxidative stress and to inhibit, in vitro, the activities of some Base Excision DNA Repair (BER) enzymes, such as hOGG1, XRCC1 and APE1, have been already established. However, the molecular mechanisms at the basis of these processes are largely unknown especially at sub-lethal doses of Cd and no information is available on the effect of Cd on the expression levels of BER enzymes. Here, we show that non-toxic treatment of neuronal cell lines, with pro-mitogenic doses of Cd, promotes a significant time- and dose-dependent down-regulation of DNA polymerase δ (POLD1) expression through a transcriptional mechanism with a modest effect on Polβ, XRCC1 and APE1. We further elucidated that the observed transcriptional repression on Polδ is acted by through competition by activated p53 on Sp1 at POLD1 promoter and by a squelching effect. We further proved the positive effect of Sp1 not only on POLD1 expression but also on Polβ, XRCC1 and APE1 expression, suggesting that Sp1 has pleiotropic effects on the whole BER pathway. Our results indicated that Cd-mediated impairment of BER pathway, besides acting on the enzymatic functions of some key proteins, is also exerted at the gene expression level of Polδ by acting on the p53-Sp1 regulatory axis. These data may explain not only the Cd-induced neurotoxic effects but also the potential carcinogenicity of this heavy metal.
Keywords
p53PolδX-Ray Repair Cross-Complementing Protein 1DNA ligase IXRCC1APE1OGG1SSBMMRMMSBER8-oxoguanine DNA glycosylaseapurinic/apyrimidinic endonuclease 1DNA polymerase βNERPolβROSSp1nucleotide excision repairmismatch repairbase excision repairCNSabasic siteNeurotoxicitycentral nervous systemsingle-strand breakmethyl methanesulfonateCadmiumReactive oxygen species
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Authors
Giulia Antoniali, Federica Marcuzzi, Elena Casarano, Gianluca Tell,