Radiation-induced DNA Damage and Transcriptional Mutagenesis in Tumor Development

描述（由申请人提供）：所有细胞的基因都受到辐射和化学品等外源性因素以及内源性自发过程的持续损伤。DMA损伤，如果不修复，可能会导致许多有害的生物学后果，包括产生突变蛋白，可以改变细胞表型。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，生理学变化以及哺乳动物细胞的肿瘤发展。绝大多数DNA损伤诱导的诱变研究是以复制为中心的，并且基于病变附近发生的DNA聚合酶错误的模型。很少有研究指出转录水平的诱变（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。该项目中提出的研究集中在两个主要领域：（i）描绘DNA修复切除途径（在细菌和哺乳动物细胞中）在转录诱变（TM）中发挥的作用，以及（ii）TM是否可以激活与哺乳动物肿瘤发展相关的突变Ras癌基因介导的信号通路。这些研究应大大增加我们的理解TM的发生和生物学相关性，以及提供重要的见解到DNA修复系统所采用的细菌和哺乳动物细胞逆转经常发生的和电离辐射诱导的DNA碱基损伤的生长和非生长条件下。

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.