DNA Polymerase Beta Variants and Cancer

DNA 聚合酶 Beta 变体与癌症

• 批准号: 10044775
• 负责人: Joann B. Sweasy
• 金额: $ 38.86万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-22 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10044775
• 关键词: Affect; African American; American; Animals; Antioxidants; Autoantibodies; B-Lymphocytes; Base Excision Repairs; Biochemical Genetics; Biological; Cell Death; Cell physiology; Child; DNA Damage; DNA Polymerase beta; DNA Repair; DNA Repair Gene; Data; Development; Disease; Disease model; Embryo; Environment; Environmental Exposure; Environmental Risk Factor; Epithelial Cells; Etiology; Exhibits; Female of child bearing age; Fibroblasts; Funding; Future; Generations; Genes; Genetic; Genetic Predisposition to Disease; Genomic Instability; Goals; Hand; Human; Immunoglobulin Somatic Hypermutation; Individual; Ionizing radiation; Knock-in Mouse; Knowledge; Lead; Link; Lupus; Malignant Neoplasms; Missense Mutation; Modeling; Mus; Nitrogen; Nonhomologous DNA End Joining; Nucleotides; Onset of illness; Organism; Oxidative Stress; Oxygen; Pathway interactions; Play; Polymerase; Process; Proteins; Reactive Oxygen Species; Research; Role; Stomach Carcinoma; Systemic Lupus Erythematosus; Testing; Tissues; V(D)J Recombination; Variant; base; chronic autoimmune disease; experimental study; gene function; genetic approach; genetic variant; insight; men; metaplastic cell transformation; model development; mouse model; mutant mouse model; novel; oxidative DNA damage; public health relevance; repair enzyme; repaired; response

 DESCRIPTION (provided by applicant): We recently constructed a POL B mutant mouse model and surprisingly these mice develop Systemic Lupus Erythematosus (SLE). POL B encodes the DNA polymerase beta protein, which functions in base excision repair (BER). BER removes DNA damage induced by ionizing radiation (IR), and reactive oxygen and nitrogen species (RONs) and an imbalance in the repair of base damage induced by IR and RONs leads to the accumulation of BER intermediates. Interestingly, individuals with SLE are unable to efficiently repair base damage induced by IR and are frequently excluded from treatment that includes IR. Our preliminary data suggest that oxidative DNA damage in our POL B defective mice results in the accumulation of BER intermediates that lead to the development of SLE. The broad long-term objective of the proposed research is to understand how aberrant DNA repair leads to SLE and to understand the interactions between genetic and environmental factors that result in SLE. In this proposal we will focus on DNA repair genes that function in BER to repair damage and that can be induced by IR and RONs. In the first aim, we will test the hypothesis that aberrant canonical base excision repair is linked to SLE in mice. In the second aim, we will test the hypothesis that aberrant co-opted DNA repair used in specialized cellular processes is linked to SLE in mice. We will use a combined biological, biochemical and genetic approach in this project. We will determine if oxidative stress-inducing agents induce SLE in our POL B mouse model and if antioxidants and genetic factors influence SLE development. These studies have significant potential to advance our fundamental understanding of how aberrant repair of DNA base damage leads to SLE and could impact treatment of this disease in the future.

 描述（由申请人提供）：我们最近构建了 POL B 突变小鼠模型，令人惊讶的是，这些小鼠患上了系统性红斑狼疮 (SLE)，POL B 编码 DNA 聚合酶 β 蛋白，该蛋白在碱基切除修复 (BER) 中发挥作用，可去除 DNA。电离辐射损伤 (IR)、活性氧和氮 (RON) 以及 IR 和 RON 引起的碱基损伤修复不平衡会导致 BER 中间体的积累。几乎没有，患有 SLE 的个体无法有效修复 IR 引起的碱基损伤，并且经常被排除在包括 IR 在内的治疗之外。我们的初步数据表明，我们的 POL B 缺陷小鼠中的氧化 DNA 损伤导致 BER 中间体的积累，从而导致 BER 中间体的积累。拟议研究的广泛长期目标是了解异常 DNA 修复如何导致 SLE，并了解导致 SLE 的遗传因素和环境因素之间的相互作用。函数于BER 修复由 IR 和 RON 引起的损伤。在第一个目标中，我们将检验异常的典型碱基切除修复与小鼠 SLE 相关的假设。 - 特定细胞过程中使用的选择性 DNA 修复与小鼠的 SLE 相关，我们将在该项目中使用生物、生化和遗传相结合的方法，我们将确定氧化应激诱导剂是否会在我们的 POL B 小鼠模型中诱导 SLE。如果抗氧化剂和遗传因素影响系统性红斑狼疮的发展，这些研究具有巨大的潜力，可以促进我们对 DNA 碱基损伤的异常修复如何导致系统性红斑狼疮的基本理解，并可能影响未来对该疾病的治疗。