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.

这项研究的广泛的长期目标是确定异常碱基切除修复 (BER)与癌症有关该项目的具体目标是： 1.为了验证细胞转化活性是Pol ~癌相关的共同特性的假设， 变体。我们将专注于尚未表征的变体，并完成 目的是表征感兴趣的Pol肿瘤相关变体。我们将使用一种结合了基因，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， 一种或多种DNA损伤剂的存在。 3.为了检验异常BER和病毒感染的组合导致 肿瘤发生在目的3中构建的小鼠将用于HPV的皮肤模型以确定是否存在病毒感染。 蛋白质与异常BER协同作用以降低肿瘤发生的速率或潜伏期或增加肿瘤发生的速率， 转移在此目的中，还将表征BER缺陷的各种其他小鼠。 4.验证microRNA在BER调控中的重要性。为了验证这个假设， BER基因中microRNA靶位点的改变导致与癌症相关的异常BER。我们将 表征内保守的微小RNA靶位点中已知的种系单核苷酸多态性 特定BER基因的3 'UTR。我们还将确定microRNA靶点是否在人类肿瘤中发生改变。