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J. Biol. Chem., Vol. 280, Issue 27, 25377-25382, July 8, 2005

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Chemical and Biological Evidence for Base Propenals as the Major Source of the Endogenous M₁dG Adduct in Cellular DNA^*

Xinfeng Zhou, Koli Taghizadeh, and Peter C. Dedon

From the Biological Engineering Division and Center for Environmental Health Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

The endogenous DNA adduct, M₁dG, has been shown to arise in vitro in reactions of dG with malondialdehyde (MDA), a product of both lipid peroxidation and 4'-oxidation of deoxyribose in DNA, and with base propenals also derived from deoxyribose 4'-oxidation. We now report the results of cellular studies consistent with base propenals, and not MDA, as the major source of M₁dG under biological conditions. As a foundation for cellular studies, M₁dG, base propenals, and MDA were quantified in purified DNA treated with oxidizing agents known to produce deoxyribose 4'-oxidation. The results revealed a consistent pattern; Fe²⁺-EDTA and -radiation generated MDA but not base propenals or M₁dG, whereas bleomycin and peroxynitrite (ONOO^–) both produced M₁dG as well as base propenals with no detectable MDA. These observations were then assessed in Escherichia coli with controlled membrane levels of polyunsaturated fatty acids (PUFA). ONOO^– treatment (2 mM) of cells containing no PUFA (defined medium with 18:0/stearic acid) produced 6.5 M₁dG/10⁷ deoxynucleotides and no detectable lipid peroxidation products, including MDA, as compared with 3.8 M₁dG/10⁷ deoxynucleotides and 0.07 µg/ml lipid peroxidation products with control cells grown in a mixture of fatty acids (0.5% PUFA) mimicking Luria-Bertani medium. In cells grown with linoleic acid (18:2), the level of PUFA rose to 54% and the level of MDA rose to 0.14 µg/ml, whereas M₁dG fell to 1.4/10⁷ deoxynucleotides. Parallel studies with -radiation revealed levels of MDA similar to those produced by ONOO^– but no detectable M₁dG. These results are consistent with base propenals as the major source of M₁dG in this model cell system.

Received for publication, March 21, 2005

^* This work was supported by National Institutes of Health Grants CA26735, CA103146, and GM59790. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Biological Engineering Division, NE47-277, MIT, Cambridge, MA 02139. Tel.: 617-253-8017; Fax: 617-324-7554; E-mail: pcdedon{at}mit.edu.

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