DNA Polymerase Beta and Cell Transformation

DNA 聚合酶 Beta 和细胞转化

• 批准号: 8307756
• 负责人: Joann B. Sweasy
• 金额: $ 34.34万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307756
• 关键词: 5' -deoxyribose phosphate lyase; Age; Base Excision Repairs; Beta Cell; Biochemical; Biological; Cell physiology; Cells; DNA; DNA Damage; DNA Polymerase beta; DNA-Directed DNA Polymerase; Excision; Funding; Genes; Genetic; Genome; Genomic Instability; Germ Lines; Human; Human Papillomavirus; Knock-in Mouse; Lesion; Link; Malignant Neoplasms; Methods; MicroRNAs; Modeling; Molecular; Monitor; Mus; Mutagenesis; Neoplasm Metastasis; Nucleotides; Phenotype; Polymerase; Property; Regulation; Research; Role; Site; Skin; Testing; Tumor Suppressor Proteins; Untranslated Regions; Variant; Viral; Viral Genes; Viral Proteins; Virus; Virus Diseases; base; carcinogenesis; cell transformation; insight; interest; metaplastic cell transformation; neutrophil; tumor; tumorigenesis

The broad long-term objective of the proposed research is to determine how aberrant base excision repair (BER) is linked to cancer. The Specific Aims of this project are: 1. To test the hypothesis that cellular transforming activity is a common property of the Pol ~ cancerassociated variants. We will focus on variants we have not yet characterized and complete the characterization of interesting Pol ~ tumor-associated variants. We will use a combined genetic, biochemical and cell biological approach to identify the mechanism of cellular transformation that is employed by the variants. 2. To test the hypothesis that cancer-associated variants induce tumorigenesis in mice. "Knock-in" mice will be constructed using standard methods. Tumorigenesis will be monitored as a function of age and also in the presence of one or more DNA damaging agents. 3. To test the hypothesis that a combination of aberrant BER and viral infection leads to tumorigenesis. The mice constructed in Aim 3 will be used in a skin model of HPV to determine if viral proteins synergize with aberrant BER to decrease the rate or latency or increase the rate of tumorigenesis or metastasis. Various other mice with deficiencies in BER will also be characterized in this aim. 4. To test the hypothesis that microRNAs are important in the regulation of BER. To test the hypothesis that alterations in microRNA target sites in BER genes results in aberrant BER that is linked to cancer. We will characterize known germ line single nucleotide polymorph isms in conserved micro RNA target sites within the 3'UTRs of specific BER genes. We will also determine if microRNA targets are altered in human tumors.

拟议研究的广泛长期目标是确定异常碱基切除修复如何 (BER) 与癌症有关。该项目的具体目标是： 1. 检验细胞转化活性是与癌症相关的 Pol ~ 的共同特性的假设 变体。我们将重点关注尚未表征的变体并完成 有趣的 Pol ~ 肿瘤相关变异的表征。我们将结合遗传、生化 和细胞生物学方法来确定细胞转化的机制 变体。 2. 检验癌症相关变异诱导小鼠肿瘤发生的假设。 “敲入”小鼠将 使用标准方法构建。肿瘤发生将作为年龄的函数进行监测，并且还可以在 一种或多种 DNA 损伤剂的存在。 3. 检验异常 BER 和病毒感染结合导致的假设 肿瘤发生。 Aim 3 中构建的小鼠将用于 HPV 皮肤模型，以确定病毒是否存在 蛋白质与异常 BER 协同作用，降低肿瘤发生率或潜伏期，或增加肿瘤发生率或 转移。在此目标中，还将对其他各种具有 BER 缺陷的小鼠进行表征。 4. 检验 microRNA 在 BER 调节中发挥重要作用的假设。为了检验以下假设 BER 基因中 microRNA 靶位点的改变会导致 BER 异常，从而与癌症相关。我们将 表征已知种系单核苷酸多态性在保守的微RNA靶位点 特定 BER 基因的 3'UTR。我们还将确定人类肿瘤中的 microRNA 靶点是否发生改变。