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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：
8860181
负责人：
Polina V Shcherbakova
金额：
$ 33.86万
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 2019-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8860181
关键词：
Affect Appearance Biochemical Biological Assay Biological Models Bypass Cancer Etiology Cell Extracts Cell Line Cell physiology Cells Characteristics DNA DNA Damage DNA Replication Damage DNA Structure DNA biosynthesis DNA lesion DNA-Directed DNA Polymerase Data Defect Development Disease Enzymes Eukaryotic Cell Event Gel Gene Mutation Generations Genome Genomic Instability Genomic Segment Goals Health Human In Vitro Incidence Induced Mutation Laboratories Lead Learning Length Lesion Location Malignant Neoplasms Measurement Measures Metabolism Modification Monitor Movement Mutagenesis Mutation Mutation Spectra Normal Cell Nucleotides Organism Pathologic Mutagenesis Pathway interactions Physiological Plant Roots Play Polymerase Preventive Process Recruitment Activity Regulation Replication Origin Research Role Saccharomyces cerevisiae Shapes Site Source Spectrum Analysis Study models System Testing Therapeutic Therapeutic Intervention Western Blotting Work Yeast Model System Yeasts environmental mutagens genetic analysis hydroxyurea improved in vivo inhibitor/antagonist mutant novel response spatiotemporal therapy outcome tool tumor progression

项目摘要

DESCRIPTION (provided by applicant): Mutations occurring spontaneously or induced by exogenous genotoxicants are a root 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. TLS polymerases are also highly error-prone when copying undamaged DNA, thus constituting a persistent source of genomic instability that needs to be controlled to avoid disease. While the mechanisms of TLS polymerase recruitment to the sites of DNA damage are understood relatively well, the mechanisms that restrict their participation in the normal replication are much less clear. The PI's laboratory has discovered that the participation of DNA polymerase ? (Pol?) in the copying of undamaged DNA is promoted by a variety factors that impede the progression of the replication, including defects in the normal replication machinery, fork stalling at natural impediments and treatment with therapeutic replication inhibitors. This proposal seeks to define the global mechanisms that regulate the extent of error-prone synthesis by Pol? in vivo in DNA damaging and physiological conditions. In Specific Aim 1, we will determine the role of checkpoint dependent elevation of dNTP pools in shaping the error signature of Pol?. In Specific Aim 2, we will determine how the contribution of Pol? to DNA synthesis is regulated by the replication dynamics and fork asymmetry. The yeast Saccharomyces cerevisiae model system will be utilized in the studies proposed in Aims 1 and 2, with the goal of using the data obtained in yeast to further advance our understanding of the mechanisms of mutagenesis in human cells. In Specific Aim 3, we will characterize the mechanism of the mutagenic response to replication defects in human cells. The proposed work will lead to a better understanding of the mutagenic processes that operate in normal cells, as well as those induced by environmental genotoxicants or therapeutic interventions. In the long run, learning to manipulate these processes will help reduce cancer incidence, delay progression and improve therapy outcome.

描述(申请人提供)：自发发生的突变或由外源基因毒物诱导的突变是癌症的根本原因。几乎所有遗传毒物诱导的突变都是由于DNA损伤和专门的跨病变合成(TLS)DNA聚合酶复制受损的DNA造成的，这些聚合酶的准确性低于正常的复制型DNA聚合酶。在复制未受损的DNA时，TLS聚合酶也非常容易出错，因此构成了基因组不稳定的持久来源，需要控制以避免疾病。虽然TLS聚合酶募集到DNA损伤部位的机制相对较好，但限制其参与正常复制的机制却不是很清楚。PI的实验室已经发现DNA聚合酶的参与？(波尔？)在复制未受损的DNA过程中，有多种因素阻碍了复制的进程，包括正常复制机制的缺陷、自然障碍下的叉子失速以及治疗性复制抑制剂的治疗。这项提案寻求定义全球机制，以规范POL？体内处于DNA损伤和生理条件下。在具体目标1中，我们将确定依赖于检查点的dNTP池提升在塑造POL？错误签名中的作用。在具体目标2中，我们将如何确定POL的贡献？DNA合成受复制动力学和分叉不对称性的调控。酿酒酵母模型系统将用于AIMS 1和2中提出的研究，目的是利用在酵母中获得的数据来进一步促进我们对人类细胞诱变机制的理解。在特定的目标3中，我们将描述人类细胞对复制缺陷的诱变反应的机制。这项拟议的工作将使人们更好地了解在正常细胞中运行的突变过程，以及由环境遗传毒物或治疗干预引起的突变过程。从长远来看，学会操纵这些过程将有助于降低癌症发病率，延缓病情发展，并改善治疗结果。