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Surveying the damage: the challenges of developing nucleic acid biomarkers of inflammation

Son, Junghyun,Pang, Bo,McFaline, Jose L.,Taghizadeh, Koli,Dedon, Peter C. Royal Society of Chemistry 2008 Molecular bioSystems Vol.4 No.9
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Epidemiological evidence points to a cause and effect relationship between chronic inflammation and human maladies such as cancer, atherosclerosis and autoimmune disease. A critical link between inflammation and disease may lie in the secretion of highly reactive oxygen and nitrogen species by macrophages and neutrophils, including hypohalous acids, nitrous anhydride, and nitrosoperoxycarbonate. Exposure of host epithelial cells to the resulting oxidation, nitration, nitrosation and halogenation chemistries leads to damage of all types of cellular molecules. Since nucleic acids sustain damage representative of the full spectrum of different chemistries and the damage likely plays a causative role in disease etiology, DNA and RNA damage products can serve as surrogates for the short-lived chemical mediators of inflammation, and as markers that provide both mechanistic understanding of the disease process and a means to quantify risk of disease. However, the very small quantities of the damaged molecules pose a challenge to the simultaneous quantification of the spectrum of lesions in the manner of proteomics or metabolomics. The goal of this Highlight is to provide an update on the chemistry of inflammation and the development of biomarkers of inflammation in the age of -omics technologies. Graphic AbstractChronic inflammation and human disease may be linked by damage to biomolecules such as DNA and RNA, with the spectrum of products reflecting the chemistry of phagocyte-generated reactive species. <IMG SRC='http://pubs.rsc.org/services/images/RSCpubs.ePlatform.Service.FreeContent.ImageService.svc/ImageService/image/GA?id=b719411k'>
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Mechanisms of Oxidation of Guanine in DNA by Carbonate Radical Anion, a Decomposition Product of Nitrosoperoxycarbonate

Lee, Young ,Ae,Yun, Byeong ,Hwa,Kim, Seog ,K.,Margolin, Yelena,Dedon, Peter ,C.,Geacintov, Nicholas ,E.,Shafirovich, Vladimir WILEY-VCH Verlag 2007 Chemistry Vol.13 No.16
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Peroxynitrite is produced during inflammation and combines rapidly with carbon dioxide to yield the unstable nitrosoperoxycarbonate, which decomposes (in part) to CO3.− and .NO2 radicals. The CO3.− radicals oxidize guanine bases in DNA through a one-electron transfer reaction process that ultimately results in the formation of stable guanine oxidation products. Here we have explored these mechanisms, starting with a spectroscopic study of the kinetics of electron transfer from 20–22mer double-stranded oligonucleotides to CO3.− radicals, together with the effects of base sequence on the formation of the end-products in runs of one, two, or three contiguous guanines. The distributions of these alkali-labile lesions were determined by gel electrophoresis methods. The cascade of events was initiated through the use of 308 nm XeCl excimer laser pulses to generate CO3.− radicals by an established method based on the photodissociation of persulfate to sulfate radicals and the oxidation of bicarbonate. Although the Saito model (Saito et al., J. Am. Chem. Soc. 1995, 117, 6406–6407) predicts relative ease of one-electron oxidations in DNA, following the trend 5′-⋅⋅⋅GGG⋅⋅⋅ > 5′-⋅⋅⋅GG⋅⋅⋅ > 5′-⋅⋅⋅G⋅⋅⋅, we found that the rate constants for CO3.−-mediated oxidation of guanines in these sequence contexts (k5) showed only small variation within a narrow range [(1.5–3.0)×107 M−1 s−1]. In contrast, the distributions of the end-products are dependent on the base sequence context and are higher at the 5′-G in 5′-⋅⋅⋅GG⋅⋅⋅ sequences and at the first two 5′-guanines in the 5′-⋅⋅⋅GGG⋅⋅⋅ sequences. These effects are attributed to a combination of initial hole distributions among the contiguous guanines and the subsequent differences in chemical reaction yields at each guanine. The lack of dependence of k5 on sequence context indicates that the one-electron oxidation of guanine in DNA by CO3.− radicals occurs by an inner-sphere mechanism. Graphic Abstract Rates of one-electron oxidation of guanine in DNA by carbonate radicals do not depend on sequence context: The sequence-dependent damage at guanine sites (see figure) is attributed to a combination of initial hole distributions among the contiguous guanines and the subsequent differences in chemical reaction yields at each guanine. <img src='wiley_img/09476539-2007-13-16-CHEM200601434-content.gif' alt='wiley_img/09476539-2007-13-16-CHEM200601434-content'>

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