MECHANISMS OF P53 MUTAGENESIS

P53 诱变机制

• 批准号: 2517693
• 负责人: GERALD P HOLMQUIST
• 金额: $ 149.08万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 1999-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2517693
• 关键词: carcinogenesis; gene mutation; molecular oncology; tumor suppressor genes

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.

我们的总体目标是剖析体细胞的分子成分 诱变并将其纳入分子的合理原理中 癌症流行病学。 我们的具体目标是确定效果 怀疑环境和内源性诱变剂对分子的影响 p53 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。 诱变指标的模式涉及碱基位置 严重损坏或修复缓慢，主要发生在 那些最不擅长修复可疑类别的患者 的病变。 我们将寻找诱变指标之间的相关性 它形成了每个诱变剂突变的模式和成分 p53 肿瘤突变数据中的签名。 我们关于诱变成分的程序主题涉及 有四个项目专注于绘制各种分子现象 只沿着一个基因p53，第一次彻底了解 这些分子现象在确定时是如何相互关联的 突变频率。 行动的主题是促进这一点 技术，从而完成分子特性的绘制。 探索诱变机制的四个项目是： 1）机制 紫外线诱导的 p53 突变； 2) 化学机理 致癌物诱导的 p53 突变； 3) 氧化损伤的机制- 诱导 p53 突变； 4) 碱基切除修复和烷基化 化疗药物引起的 p53 损伤。 这四个实验项目由三个核心支持。 第一个 核心将是协调和共享通用试剂并开发 并自动化连接介导的 PCR，第二个是针对组织 文化，第三个是项目的管理。