A method is being developed for examining individual humans (or rats) for DNA damage by analyzing damaged DNA bases (excised from DNA by repair enzymes) which appear in urine. We have found several oxidized thymine derivatives in human and rat urine and we will investigate the utility of these bases as markers for metabolic contributions to oxidative DNA damage leading to aging and cancer. We will study the role of agents which might increase this damage, such as radiation or increased calorie intake, and agents protecting against such damage, such as dietary antioxidants. We are investigating the role of oxidative processes in cancer (and aging) and the mechanism by which cells induce the protective enzymes against active forms of oxygen. We are investigating hitherto unrecognized systems that cells have for protecting against stresses such as that from oxygen damage. The role of modified nucleosides in tRNA, and small molecules such as AppppA, will be studied as signals for altering cells to oxidative damage. We propose to improve both the detection and analysis of mutagens by developing a set of bacterial strains, each of which reverts by only one specific base-pair change so that the set of strains will be diagnostic for the spectrum of mutations done by any mutagen and be much more sensitive for detecting mutagens. We will use these strains for investigating new important contributors to DNA damage and for aiding in understanding the relation of mutagenesis to carcinogenesis. The main research focus is in identifying the important mutagens damaging human DNA, the natural defense mechanisms protecting us from them, and the consequences of DNA damage for cancer and aging.
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