title: Cadmium treatment suppresses DNA polymerase δ catalytic subunit gene expression by acting on the p53 and Sp1 regulatory axis.
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.
authors.affiliation: Laboratory of Molecular Biology and DNA Repair, Department of Medical and Biological Sciences, University of Udine, 33100 Udine, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Antoniali
authors.affiliation: Laboratory of Molecular Biology and DNA Repair, Department of Medical and Biological Sciences, University of Udine, 33100 Udine, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Marcuzzi
authors.affiliation: Laboratory of Molecular Biology and DNA Repair, Department of Medical and Biological Sciences, University of Udine, 33100 Udine, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Casarano
authors.affiliation: Laboratory of Molecular Biology and DNA Repair, Department of Medical and Biological Sciences, University of Udine, 33100 Udine, Italy. Electronic address: gianluca.tell@uniud.it.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tell
mesh_terms: D002104:Cadmium / Q000494:pharmacology / Q000633:toxicity*; D063646:Carcinogenesis / Q000139:chemically induced; D002273:Carcinogens / Q000633:toxicity*; D020134:Catalytic Domain / Q000235:genetics; D045744:Cell Line, Tumor; D004258:DNA Polymerase III / Q000037:antagonists & inhibitors* / Q000235:genetics; D019951:DNA Polymerase beta / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation; D004785:Environmental Pollutants / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D009498:Neurotoxins / Q000633:toxicity*; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D002273:Carcinogens; D004268:DNA-Binding Proteins; D004785:Environmental Pollutants; D009498:Neurotoxins; D016329:Sp1 Transcription Factor; C108209:SP1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; D002104:Cadmium; C434055:POLD1 protein, human; D004258:DNA Polymerase III; D019951:DNA Polymerase beta; D045643:DNA Repair Enzymes
keywords: Base excision repair; Cadmium; Neurotoxicity; P53; Sp1