Radiation-induced DNA Damage and Transcriptional Mutagenesis in Tumor Development

肿瘤发展中辐射诱导的 DNA 损伤和转录突变

基本信息

批准号：
7667814
负责人：
Paul William Doetsch
金额：
$ 29.07万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-01 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7667814
关键词：
8-Oxoguanine DNA Glycosylase Address Area Bacteria Base Excision Repairs Biological Biological Assay Cell Culture System Cell Cycle Progression Cell Death Cells Chemicals Cockayne Syndrome Codon Nucleotides DNA DNA Damage DNA Repair DNA Repair Pathway DNA-Directed DNA Polymerase DNA-Directed RNA Polymerase Development Embryo Endonuclease V Epithelial Cells Event Excision Excision Repair Fibroblasts Foundations Future Genes Genetic Genetic Transcription Goals Growth Human Individual Interphase Cell Ionizing radiation Knock-out Lead Left Lesion Luciferases Lung Mammalian Cell Mediating Mismatch Repair Modeling Mus Mutagenesis Nucleotide Excision Repair OGG1 gene Oncogene Proteins Pathway interactions Phase Phenotype Phosphorylation Phosphotransferases Physiology Play Population Positioning Attribute Process Production Proteins RAS genes Radiation Radiation Induced DNA Damage Reporter Research Personnel Rodent Role Sequence Analysis Serum Signal Pathway Signal Transduction Site System Transcript Transcription-Coupled Repair Tumor Promotion Uracil XPGC protein base cell growth cell type design insight mutant programs ras Oncogene ras Proteins repair enzyme repaired research study tumor

项目摘要

DESCRIPTION (provided by applicant): The genes of all cells are continuously damaged by extrinsic agents such as radiation and chemicals as well as endogenous, spontaneous processes. DMA damage, if left unrepaired, can result in a number of deleterious biological consequences, including the production of mutant proteins that can change the cellular phenotype. Delineating the processes that generate mutant proteins is of great importance for our understanding of the endpoints of genetic damage which include cell death, changes in physiology and, in the case of mammalian cells, tumor development. The vast majorities of DNA damage-induced mutagenesis studies are replication-centric and are based on models of DNA polymerase errors occurring in the vicinity of the lesion. Few studies have addressed the possibility that mutagenesis at the level of transcription (via RNA polymerase encounters with DNA damage) may also be an important pathway for generating mutant proteins, particularly in non-dividing cells. The studies proposed in this project are focused on two major areas: (i) the delineation of the roles that DNA repair excision pathways (in bacterial and mammalian cells) play in transcriptional mutagenesis (TM), and (ii) whether TM can activate a mutant Ras oncogene-mediated signaling pathway related to mammalian tumor development. These studies should substantially increase our understanding of the occurrence and biological relevance of TM as well as provide important insights into the DNA repair systems employed by bacterial and mammalian cells for reversing frequently occurring and ionizing radiation-induced DNA base damages under both growth and non-growth conditions.

描述（由申请人提供）：所有细胞的基因都会受到外在因素（例如辐射和化学物质）以及内源性自发过程的持续损害。 DMA 损伤如果不加以修复，可能会导致许多有害的生物学后果，包括产生可以改变细胞表型的突变蛋白。描述产生突变蛋白的过程对于我们理解遗传损伤的终点非常重要，这些终点包括细胞死亡、生理变化，以及哺乳动物细胞的肿瘤发展。绝大多数 DNA 损伤诱导的突变研究都是以复制为中心的，并且基于损伤附近发生的 DNA 聚合酶错误模型。很少有研究表明转录水平上的诱变（通过 RNA 聚合酶遇到 DNA 损伤）也可能是产生突变蛋白的重要途径，特别是在非分裂细胞中。该项目提出的研究主要集中在两个主要领域：(i) 描述 DNA 修复切除途径（在细菌和哺乳动物细胞中）在转录诱变 (TM) 中所起的作用，以及 (ii) TM 是否可以激活突变Ras癌基因介导的与哺乳动物肿瘤发展相关的信号通路。这些研究应该大大增加我们对 TM 的发生和生物学相关性的理解，并为细菌和哺乳动物细胞所使用的 DNA 修复系统提供重要的见解，以逆转生长和非生长条件下经常发生的电离辐射引起的 DNA 碱基损伤。生长条件。