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Originally published In Press as doi:10.1074/jbc.M503079200 on May 5, 2005
J. Biol. Chem., Vol. 280, Issue 27, 25377-25382, July 8, 2005
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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Copyright © 2005 by the American Society for Biochemistry and Molecular Biology.
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