MECHANISMS OF P53 MUTAGENESIS

我们的总体目标是剖析体细胞的分子组成 突变，并将这些纳入分子的合理理论基础 癌症流行病学。我们的具体目标是确定 疑似环境和内源性诱变剂对分子的影响 P53基因突变的流行病学。使用各种诱变剂，我们将绘制 P53基因每个核苷酸位置的突变模式 外显子5-9。突变指标的模式涉及碱基位置 严重受损或修复缓慢，主要发生在 那些最不擅长修复疑似类的患者 损伤的数量。我们将寻找诱变指标之间的关联 它形成了每个诱变剂的突变模式和成分 在P53肿瘤突变数据中签名。 我们关于诱变成分的程序性主题包括 有四个项目专注于绘制各种分子现象 只有一个基因，P53，并首次彻底了解 这些分子现象是如何相互关联的 突变频率。行动的主题是促进这一点 技术，这样就可以完成分子性质的映射。 探索诱变机制的四个项目是：1)机制 紫外光诱导P53基因突变的研究：2)化学机制 致癌物诱导的P53突变；3)氧化损伤的机制- 诱发p53突变；4)碱基切除修复和烷化 化疗药物所致的P53损伤。 这四个实验项目由三个核心支持。第一 CORE将协调和共享通用试剂并用于开发 而自动化连接介导的聚合酶链式反应，第二个是组织 文化，第三是项目的管理。

Our overall goal is to dissect the molecular components of somatic mutagenesis and incorporate these into a sound rationale for the molecular epidemiology of cancer. Our specific goal is to determine the effect of suspected environmental and endogenous mutagens on the molecular epidemiology of p53 mutations. Using a variety of mutagens, we will map patterns of mutagenesis along each nucleotide position of the p53 gene exons 5-9. The patterns of mutagenesis metrics involve base positions which are heavily damaged or slowly repaired and occur predominantly in those patients who are least proficient at repairing the suspected class of lesions. We will search for a correlation between a mutagenesis metric which forms the pattern and components of each mutagen's mutational signature in the p53 tumor mutation data. Our procedural theme for relating the components of mutageneses involves having four projects concentrating on mapping various molecular phenomena along only one gene, p53, and to thoroughly understand for the first time how these molecular phenomena are interrelated in their determination of mutation frequency. The theme of operations is to facilitate this technology so that mapping of molecular properties will get accomplished. The four projects exploring the mutagenesis mechanisms are: 1) Mechanisms of Ultraviolet Light-Induced p53 Mutations; 2) Mechanisms of Chemical Carcinogen-Induced p53 Mutations; 3) Mechanisms of Oxidative Damage- Induced p53 Mutations; and 4) Base Excision Repair and Alkylating Chemotherapeutic Agent-Induced p53 Damage. The four experimental projects are supported by three cores. The first core will be coordinating and sharing common reagents and for developing and automating the ligation-mediated PCR, the second is for tissue culture, and the third is for administration of the program.