GENOMIC DISTRIBUTION AND PHYLOGENY OF DNA REPAIR

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The overall goal of this proposal is to study the genotoxicity and repair of oxidized DNA bases. The specific aims are two. The first is to determine whether base excision repair (Dna glycosylase mediated) is selective in actively transcribed genes as has been shown for the nucleotide excision repair (multi-protein endo-nuclease) of UV dimers. We will study the repair of 5-Hydroxymethyluracil (HmUra) as an example of a lesion which does not block transcription. Secondly, we will study the phylogenetic distribution of the repair enzymes, HmUra-DNA glycosylase and 5-hydroxymethylcytosine (HmCyt)-DNA glycosylase. Both of these activities are present in mammalian tissue and are absent from bacteria. These are the only known DNA glycosylase activities showing this phylogenetic dissociation. A study of their phylogenetic distribution will clarify the susceptibility of methylcytosine and thymine residues to endogenous oxidative stress. Oxidative damage to DNA has been suggested to play a role in the etiology of cancer and aging. Our approach is a direct biochemical and phylogenetic study addressed at evaluating this hypothesis.