权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Translesion Synthesis DNA Polymerases and Genome Instability

跨损伤合成 DNA 聚合酶和基因组不稳定性

基本信息

批准号：
8463180
负责人：
Polina V Shcherbakova
金额：
$ 22.46万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8463180
关键词：
Acute Affect Alkylating Agents Area Benzo(a)pyrene Biochemical Biological Models Bypass Cancer Etiology Cell Extracts Cells Chronic DNA DNA Damage DNA Replication Damage DNA Sequence Analysis DNA Structure DNA biosynthesis DNA lesion DNA-Directed DNA Polymerase Data Defect Development Dose Electrophoresis Environmental Risk Factor Epoxy Compounds Event Exposure to Funding Gene Mutation Generations Genes Genetic Genetic Polymorphism Genomic Instability Goals Health Human Incidence Individual Induced Mutation Knowledge Laboratories Lead Length Lesion Malignant Neoplasms Mediating Modification Mutagenesis Mutation Mutation Spectra Plant Roots Plasmids Play Polymerase Positioning Attribute Post-Translational Protein Processing Predisposition Preventive Proteins Publishing Research Role Saccharomyces cerevisiae Single Nucleotide Polymorphism Site Source System Testing Ubiquitin Work Yeasts base cancer prevention cost environmental mutagens in vivo interest mutant novel research study response tool two-dimensional ultraviolet irradiation

项目摘要

DESCRIPTION (provided by applicant): Mutations occurring spontaneously or induced by environmental genotoxicants are a major initiating cause of cancer. Nearly all genotoxicant-induced mutations result from DNA damage and replication of the damaged DNA by specialized translesion synthesis (TLS) DNA polymerases that are less accurate than normal replicative DNA polymerases. The PI's laboratory has recently discovered that TLS DNA polymerase ??(Pol ?) also becomes a powerful source of spontaneous mutations in cells with defects in normal replication machinery. The mechanisms regulating the recruitment of Pol ? in response to replication defects, however, remain obscure. This proposal seeks to further investigate the novel role of Pol ? in mutagenesis in the absence of overt DNA damage. The long-term goal of this study is to define the mechanisms by which genetic and environmental factors regulate the contribution of error-prone DNA polymerases to mutagenesis. The yeast Saccharomyces cerevisiae model system will be utilized in the proposed studies, with the goal of using the data obtained in yeast to further advance our understanding of the mechanisms of mutagenesis in human cells. The Specific Aims of this project are: (1) To define the role of TLS polymerases in the mutagenic response to replication defects; (2) To define the role of the polymerase accessory factor PCNA in the mutagenic response to replication defects; and (3) To determine the effects on the rate of mutation accumulation of a combination of the replication defects with environmental genotoxicant exposure. The proposed work will lead to a better understanding of the mechanisms by which DNA replication defects cause mutations. This information will be important for the development of effective approaches to cancer prevention, particularly in individuals carrying mutations or polymorphisms in DNA replication genes.

描述（由申请人提供）：自发发生或由环境遗传毒物诱导的突变是癌症的主要起始原因。几乎所有的遗传毒性诱导的突变都是由DNA损伤和受损DNA通过特异性跨损伤合成（TLS）DNA聚合酶的复制引起的，所述TLS DNA聚合酶比正常的复制型DNA聚合酶更不精确。PI的实验室最近发现TLS DNA聚合酶？？(Pol ?)在正常复制机制有缺陷的细胞中，也成为自发突变的强大来源。调节Pol的招募的机制？然而，对复制缺陷响应仍然不清楚。这项建议旨在进一步研究新的作用波尔？在没有明显DNA损伤的情况下进行诱变。本研究的长期目标是确定遗传和环境因素调节易错DNA聚合酶对诱变的贡献的机制。酵母酿酒酵母模型系统将用于拟议的研究，目的是使用在酵母中获得的数据，以进一步推进我们对人类细胞诱变机制的理解。本项目的具体目的是：（1）确定TLS聚合酶在复制缺陷致突变反应中的作用;（2）确定聚合酶辅助因子PCNA在复制缺陷致突变反应中的作用;（3）确定复制缺陷与环境遗传毒物暴露组合对突变累积速率的影响。拟议的工作将导致更好地了解DNA复制缺陷导致突变的机制。这些信息对于开发有效的癌症预防方法非常重要，特别是在DNA复制基因中携带突变或多态性的个体中。