Enzymatic Removal of O6-Ethylguanine versus Stability of O4-Ethylthymine in the DNA of Rat Tissues Exposed to the Carcinogen Ethylnitrosourea: Possible Interference of Guanine-O6 Alkylation with 5-Cytosine Methylation in the DNA of Replicating Target Cells
2014
Müller, Rolf | Rajewsky, Manfred F.
In order to compare the kinetics of their enzymatic elimination from the DNA of liver, kidney, lung, and brain, the alkylation products O⁴-ethyl-2'-deoxythym idine (O⁴-EtdThd) and O⁶-ethyl- 2'-deoxyguanosine (O⁶-EtdGuo) were quantitated by competitive radioimmunoassay over a period of 48 h after a single pulse of the carcinogen N -ethyl-N-nitrosourea (EtNU) applied i.p. to 10 and 28-day-old BDIX-rats. The content of O⁴-EtdThd in the DNA of all organs analyzed remained stable, while O⁶-EtdGuo (initially formed in DNA with 3 - 4 times higher frequency than O⁴-EtdThd) was rapidly removed from the DNA of liver, followed by lung and kidney, but persisted strongly in the DNA of brain. At 48 h after the EtNU -pulse, the O⁴-EtdThd content of liver DNA exceeded the O⁶-EtdGuo content by about a factor of 4. Since both O⁶-EtdG uo and O⁴-EtdThd are miscoding DNA lesions, the lack of enzymatic removal of O⁴-EtdThd is surprising in view of the apparent concern of cells to restore the integrity of the Opposition of guanine. Genetic consequences more specifically connected with the formation of O⁶-alkylguanine in DNA might be considered, e.g., possible alterations of gene expression via interference with enzymatic 5-cytosine methylation in 5'-CpG-3' sequences of newly replicated DNA
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