DNA Polymerase Beta Variants and Cancer

 描述(由申请人提供)：我们最近构建了一个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。BER可以清除电离辐射(IR)引起的DNA损伤，而活性氧和氮物种(RON)以及IR和RONS引起的碱基损伤修复失衡导致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缺陷小鼠的氧化DNA损伤导致BER中间体的积累，从而导致SLE的发展。这项拟议研究的长期目标是了解DNA修复异常如何导致系统性红斑狼疮，并了解导致系统性红斑狼疮的遗传和环境因素之间的相互作用。在这个提案中，我们将重点介绍DNA修复基因，这些基因在BER中发挥修复损伤的功能，并且可以被IR和RONS诱导。在第一个目标中，我们将检验这样一个假设，即异常的典型碱基切除修复与小鼠系统性红斑狼疮有关。在第二个目标中，我们将测试在特殊细胞过程中使用的异常共选DNA修复与小鼠系统性红斑狼疮有关的假设。我们将在这个项目中使用生物、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。这些研究有很大的潜力促进我们对DNA碱基损伤的异常修复如何导致SLE并可能影响未来这种疾病的治疗的基本理解。

 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.