Journal
CHEMICAL RESEARCH IN TOXICOLOGY
Volume 19, Issue 5, Pages 614-621Publisher
AMER CHEMICAL SOC
DOI: 10.1021/tx060025x
Keywords
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Funding
- NCI NIH HHS [R01 CA096906, R01 CA101864, R01 CA96906, R01 CA096906-04, R01 CA096906-05, R01 CA101864-04, R01 CA101864-03] Funding Source: Medline
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Reactive oxygen species (ROS) can be induced by both endogenous and exogenous processes, and they can damage biological molecules including nucleic acids. It was shown that X- or gamma-ray irradiation of aqueous solutions of DNA, during which (OH)-O-center dot is one of the major ROS, can lead to the formation of intrastrand cross-link lesions where the neighboring nucleobases in the same DNA strand are covalently bonded. Previous P-32-postlabeling studies suggested that the intrastrand cross- link lesions may arise from Fenton reaction, which also induces the formation of (OH)-O-center dot; the structures of the proposed intrastrand cross- link lesions, however, have not been determined. Here, we showed for the first time that the treatment of calf thymus DNA with Cu(II)/H2O2/ascorbate could lead to the formation of an intrastrand cross-link lesion, i.e., G boolean AND T, where the C8 of guanine is covalently bonded to the neighboring 3'- thymine through its methyl carbon. LC-MS/ MS quantification results showed dose-responsive formation of G boolean AND T. In addition, the yield of the intrastrand cross- link was approximately 3 orders of magnitude lower than those of commonly observed single-base lesions, that is, 8-oxo-7,8-dihydro-2'- deoxyguanosine, 5-( hydroxymethyl)2'- deoxyuridine, and 5-formyl-2'-deoxyuridine. The induction of intrastrand cross- link lesion in calf thymus DNA by Fenton reagents in vitro suggests that this type of lesion might be formed endogenously in mammalian cells.
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