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：
7194447
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/7194447
关键词：
8-Oxoguanine DNA Glycosylase 8-oxoguanine Address Area Bacteria Base Excision Repairs Biological Biological Assay Cell Culture System Cell Cycle Progression Cell Death Cells Chemicals Class Cockayne Syndrome Codon Nucleotides Condition DNA DNA Damage DNA Repair DNA Repair Pathway DNA-Directed DNA Polymerase DNA-Directed RNA Polymerase Development ERCC5 gene Embryo End Point Endonuclease V Epithelial Cells Event 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 Numbers 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 Rate 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）：所有细胞的基因均被辐射和化学物质以及内源性的自发过程等外在药物不断损害。 DMA损伤（如果未修复）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对遗传损伤的终点的理解至关重要，包括细胞死亡，生理学的变化以及哺乳动物细胞的变化，肿瘤发育。绝大多数DNA损伤诱导的诱变研究都是以复制为中心的，并且基于病变附近发生的DNA聚合酶误差的模型。很少有研究解决了在转录水平（通过RNA聚合酶遇到DNA损伤）处的诱变也可能是产生突变蛋白，尤其是在非分裂细胞中的重要途径。该项目中提出的研究集中在两个主要领域：（i）在转录诱变（TM）（TM）中起作用DNA修复切除途径（在细菌和哺乳动物细胞中）的作用的描述，以及（ii）TM是否可以激活与哺乳动物的突变体Ras Oncogene介导的信号传导途径与哺乳动物瘤的发展相关。这些研究应大大提高我们对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采用的DNA修复系统提供重要见解，以逆转在生长和非增长条件下经常发生的经常发生和电离辐射诱导的DNA碱基损害。