Translesion Synthesis DNA Polymerases and Genome Instability

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。公共卫生相关性：基因突变是癌症发展的关键起始步骤。Pol？在突变产生中起主要作用。本提案旨在研究控制Pol？致突变活性的机制。这项研究将有助于更好地了解癌症发病率背后的事件，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.