Base damage

Brcimer, L.H. (1990). Molecular mechanisms of oxygen radical carcinogenesis and mutagenesis. The role of DNA base damage. Mol. Carcinogen. 3, 188-197. 

Dizdaroglu, M. (1993). Quantitative determination of oxidative base damage in DNA by stable isotope-dilution mass spectrometry. FEBS Lett. 315, 1-6. 

Dizdaroglu, M., Nackerdien, Z., Chao, B.C., Gajewski, E. and Rao, G. (1991b). Chemical nature of in vivo DNA base damage in hydrogen peroxide-treated mammalian cells. Arch. Biochem. Biophys. 285, 388-390. 

Kasprzak, K.S., Diwan, B.A., Rice, J.M., Misra, M., Riggs, C.W., Olinski, R and Dizdaroglu, M. (1992). Nickel(II)-mediated oxidative DNA base damage in renal and hepatic chromatin of pregnant rats and their fetuses. Possible relevance to carcinogenesis. Chem. Res. Tox. 5, 810-815. 

Radicals can react with bases via hydrogen atom abstraction or, more commonly, by addition to the pi bonds in the heterocyclic nucleobases (Scheme 8.1). These reactions have been extensively studied in the context of hydroxyl radical (HO ), which is generated by y-radiolysis of water. When DNA is exposed to the hydroxyl radical, approximately 80% of the reactions occur at the bases. Many base damage products arising from the reaction hydroxyl radical with DNA have been characterized (Fig. 8.2). ... 

Radical attack yields nucleobase radical adducts that must undergo either oxidation or rednction to yield a stable final prodnct. The cellular oxidant in these reactions may be molecnlar oxygen or high-valent transition metal ions (e.g., Fe ), while the reduc-tant may be either thiols, snperoxide radical, or low-valent transition metal ions (e.g., Fe ). In many cases, the base remains largely intact and the seqnence of chemical events can be readily inferred. In some other cases, more extensive base decomposition occurs. Here, we will consider a set of representative examples that provide a framework for understanding virtnally all radical-mediated base damage reactions. 

Measurement, chemistry, and biological importance of oxidative DNA base damage ... 

A specific approach for the measurement of base damage to DNA involves the hydrolysis of DNA into monomeric units. Acidic hydrolysis leads to the release of bases while enzymatic treatment yields nucleosides. The resulting mixture of lesions together with the overwhelming presence of normal bases or nucleosides is resolved by chromatography. The targeted damage is then quantified by use of specific detection systems. 

HPLC-MS/MS has been applied to the quantification of several types of radical-induced base damage within DNA [16, 17, 120-122]. In particular,... 

DNA base damage is also frequent after radiation (Ward, 1986). As compared to ssb, this DNA lesion is regarded as a possible source of mutation and is repaired through specific DNA repair pathways, such as base excision repair and nucleotide excision repair. 

Trewick, S.C., Henshaw, T.F., Hausinger, R.P., Lindahl, T. and Sedgwick, B. (2002) Oxidative demethylation hjEscherichia coli AlkB directly reverts DNA base damage. Nature, 419, 174-178. 

The formation and identification of the free bases, and subsequently other types of base damage, have been reported by Swarts et al. [101,174-176]. These papers present the first measurements of specific products produced by the direct effect in DNA. Equally important, the sample type and preparation correspond closely to that employed in a wide range of EPR studies that identify free radical intermediates trapped on DNA [14,30,83]. 

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