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，这些小鼠发展为系统性红斑狼疮（SLE）。POL B编码DNA聚合酶β蛋白，其在碱基切除修复（BER）中起作用。BER消除由电离辐射（IR）和活性氧和氮物质（RON）诱导的DNA损伤，并且由IR和RON诱导的碱基损伤修复的不平衡导致BER中间体的积累。有趣的是，SLE患者不能有效地修复IR引起的碱基损伤，并且经常被排除在包括IR的治疗之外。我们的初步数据表明，在我们的POL B缺陷小鼠中的氧化性DNA损伤导致BER中间体的积累，从而导致SLE的发展。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的遗传和环境因素之间的相互作用。在这个建议中，我们将重点放在DNA修复基因，在BER中的功能，以修复损伤，并可以诱导IR和RON。在第一个目标，我们将测试的假设，异常的典型碱基切除修复与SLE小鼠。在第二个目标，我们将测试的假设，在专门的细胞过程中使用的异常增选DNA修复与SLE小鼠。我们将在这个项目中使用生物学、生物化学和遗传学相结合的方法。我们将确定氧化应激诱导剂是否在我们的POL B小鼠模型中诱导SLE，以及抗氧化剂和遗传因素是否影响SLE的发展。这些研究具有重要的潜力，以促进我们的基本理解如何异常修复DNA碱基损伤导致系统性红斑狼疮，并可能影响这种疾病的治疗在未来。