Identification of 3,N(4)-etheno-5-methyl-2'-deoxycytidine in human DNA: a new modified nucleoside which may perturb genome methylation |
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Authors: | Nair Jagadeesan Godschalk Roger W Nair Urmila Owen Robert W Hull William E Bartsch Helmut |
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Affiliation: | German Cancer Research Center (DKFZ) , Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. |
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Abstract: | Methylation of cytidine at dCpdG sequences regulates gene expression and is altered in many chronic inflammatory diseases. Inflammation generates lipid peroxidation (LPO) products which can react with deoxycytidine, deoxyadenosine, and deoxyguanosine in DNA to form pro-mutagenic exocyclic etheno-nucleoside residues. Since 5-methyl-2'-deoxycytidine (5mdC) residues exhibit increased nucleophilicity at N3, they should be even better targets for LPO products. We synthesized and characterized 3,N(4)-etheno-5-methyl-2'-deoxycytidine-3'-phosphate and showed that LPO products can indeed form the corresponding etheno-5mdC (ε5mdC) lesion in DNA in vitro. Our newly developed (32)P-postlabeling method was subsequently used to detect ε5mdC lesions in DNA from human white blood cells, lung, and liver at concentrations 4-10 times higher than that observed for etheno adducts on nonmethylated cytidine. Our new detection method can now be used to explore the hypothesis that this DNA lesion perturbs the DNA methylation status. |
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