GENOMIC DISTRIBUTION AND PHYLOGENY OF DNA REPAIR

这项建议的总体目标是研究遗传毒性和修复 氧化的DNA碱基。具体目标有两个。第一个是 确定碱基切除修复(DNA糖基酶介导)是否 在活跃转录的基因中具有选择性，这一点已经在 紫外线二聚体的核苷酸切除修复(多蛋白核酸内切酶)。我们 将研究5-羟甲基尿嘧啶(HmUra)的修复作为一个例子 不阻碍转录的病变。其次，我们将研究 修复酶、HmUra-DNA糖基酶和HmUra-DNA糖基酶的系统发育 5-羟甲基胞嘧啶(HmCyt)-DNA糖基化酶。这两项活动 存在于哺乳动物组织中，而不存在于细菌中。这些是 唯一已知的显示这一系统发育的DNA糖基酶活性 解离。对它们的系统发育分布的研究将澄清 甲基胞嘧啶和胸腺嘧啶残留量对内源性的敏感性 氧化应激。DNA的氧化损伤被认为在 在癌症和衰老的病因学中的作用。我们的方法是直接的 生化和系统发育研究致力于评估这一假说。

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.