Translesion Synthesis DNA Polymerases and Genome Instability

描述(由申请人提供)：自发发生的突变或由环境遗传毒物诱导的突变是癌症的主要起因。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。PI的实验室最近发现了TLS DNA聚合酶？(Pol？)也成为具有正常复制机制缺陷的细胞自发突变的强大来源。POL招募的监管机制是什么？然而，对于复制缺陷的响应仍然是模糊的。这项提议旨在进一步调查波尔？在没有明显DNA损伤的情况下进行突变。这项研究的长期目标是确定遗传和环境因素调节容易出错的DNA聚合酶对突变的贡献的机制。酿酒酵母模型系统将用于拟议的研究中，目的是利用在酵母中获得的数据来进一步加深我们对人类细胞诱变机制的理解。本项目的具体目标是：(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增殖细胞核抗原在复制缺陷致突变反应中的作用；以及(3)确定复制缺陷与环境遗传毒物暴露的组合对突变累积速率的影响。这项拟议的工作将有助于更好地理解DNA复制缺陷导致突变的机制。这些信息将对开发有效的癌症预防方法非常重要，特别是在携带DNA复制基因突变或多态的个体中。公共卫生相关性：基因突变是癌症发展的关键启动步骤。在突变的产生中，POL？起着重要的作用。该提案旨在研究控制POL？诱变活性的机制。这项研究将有助于更好地了解癌症发病率背后的事件，并从长远来看，有助于开发有效的预防方法。

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. PUBLIC HEALTH RELEVANCE: Gene mutation is a key initiating step in the development of cancer. A major role in the generation of mutations is played by Pol ?. This proposal seeks to investigate the mechanisms that control the mutagenic activity of Pol ?. This research will lead to a better understanding of the events underlying the incidence of cancer, and, in the long run, help develop effective preventive approaches.