DNA Polymerase Beta and Cell Transformation

DNA 聚合酶 Beta 和细胞转化

• 批准号: 7726052
• 负责人: Joann B. Sweasy
• 金额: $ 34.93万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7726052
• 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.

所提出的研究的长期目标是确定异常基底切除如何修复