The Dedon research group seeks to understand the chemical etiology of human disease, with the long-term goals of developing diagnostic tools and therapies. Using both data- and hypothesis-driven approaches, the research team develops ultra-sensitive bioanalytical tools to characterize and quantify normal and damaged biomolecules in cells and tissues and to interrogate biochemical networks and systems. The current research program has a broad theme of nucleic acid chemistry and biology with a focus on microbial pathogens, inflammation and cancer in four major projects. Inflammation and chemical immunology. The Dedon research group has a long-standing interest in understanding the link between chronic inflammation and human diseases, such as cancer. Activation of the innate immune system by infection or tissue damage leads to the generation of highly reactive oxygen and nitrogen species, such as nitric oxide, superoxide, peroxynitrite and hydrogen peroxide. While intended to combat the invading microbes, these reactive species damage virtually all types of biological molecules in surrounding host cells. Chan et al. J. Am. Chem. Soc. 132: 6145, 2010; Taghizadeh et al. Nat. Prot. 3: 1287, 2010, 2008; Lonkar and Dedon Int. J. Cancer Dec 2 epublication ahead of print. Fate and transport of DNA damage products. A major hurdle to the development of damaged biomolecules as biomarkers is our lack of understanding of the metabolic fate of the damage products following their formation. With much of the chemistry of DNA, RNA, protein and lipid damage now well characterized, we have now turned our attention to the biological fates of these damage products in terms of their metabolism and excretion. Jiang et al. Proc. Natl. Acad. Sci. USA 104: 60-65, 2007. RNA 2° modifications in cellular response pathways. There are >100 different ribonucleoside structures identified in the tRNA and rRNA of prokaryotes and eukaryotes. Using a novel mass spectrometry-based platform for identifying and quantifying all of the RNA modifications in an organism, we recently discovered that these modifications function as a system to control translation of critical proteins in response to cell stimuli and that their biosynthetic pathways are critical to cell survival in response to toxic exposures. We have now embarked on a study of RNA modifications in variety of pathogenic microbes, including Helicobacter, mycobacteria (tuberculosis) and malarial parasites. The goal is to characterize the role of RNA modifications in the response of microbial pathogens to chemical mediators of inflammation generated during the human immune response. Chan et al. PLoS Genetics 6: e1001247, 2010. Phosphorothioate modifications of bacterial DNA. Phosphorothioate (PT) modification of the DNA backbone involves replacement of a non-bridging phosphate oxygen with a sulfur atom. PT modification of DNA has long been known as a synthetic modification that stabilizes oligodeoxynucleotides against nuclease degradation. However, we recently discovered that PT modifications occur naturally in DNA from bacteria harboring dnd genes, with a frequency and sequence specificity consistent with a new type of restriction-modification system. Studies are underway to further define the biological function of PT modifications in bacteria. Wang et al. Nat. Chem. Biol. 3: 709, 2007.