Oxidative damage to DNA and proteins. Free

PL01-02

The inflammatory response generates a constellation of reactive oxidants, electrophiles, lipid mediators, cytokines, etc. These species contribute to pathogen killing as well as activation and resolution of inflammation. Collateral damage to adjacent cell types contributes to tissue injury. A broad spectrum of damage is induced in DNA as a result of direct oxidation or nitration of DNA bases or the deoxyribosyl backbone. Damage also results from coupling to reactive electrophiles generated as products of lipid oxidation. The genotoxicity and mutagenicity of many of these types of DNA damage have been evaluated in site-specific experiments utilizing vectors that contain a single adduct at a defined position. For example, 8-oxo-7,8-dihydro-2'-deoxyguanosine is the most abundant product of DNA oxidation but it is weakly mutagenic when compared to some minor products derived from it. A survey of the biological activities of oxidant-induced lesions will be presented. The other important target of oxidation is protein but much less is known about the chemistry and biology of protein modification compared to DNA modification. This situation is being rectified rapidly because of the power of mass spectrometry-based proteomics, increasingly sophisticated protein sequence databases, and the development of novel chemistry with which to identify modified proteins. Analysis of the biological responses cells exhibit toward oxidants and electrophiles indicate that discrete signaling pathways are triggered as a result of protein modification. Some protein modification, especially at low oxidant/electrophile concentrations, activates signaling designed to protect the cell from further damage. Comprehensive genomic and proteomic analysis suggests that multiple signaling pathways are engaged following oxidant/electrophile exposure including heat shock, antioxidant response, endoplasmic reticulum stress, etc. The chemistry and biological consequences of protein modification will be considered.