DNA Polymerase Beta Variants and Cancer

描述(申请人提供)：聚合酶β变异体和癌症。摘要：DNA聚合酶β在碱基切除修复(BER)中发挥作用，BER对修复内源性DNA损伤和电离辐射等物质引起的损伤具有重要作用。这项拟议研究的广泛长期目标是了解异常的BER与癌症的发生和使用包括电离辐射在内的药物治疗癌症之间的联系。该申请由三个具体目标组成。第一个目标是测试一种与癌症相关的POLβ变异体在小鼠体内诱导肿瘤形成的假设。第二个目的是验证波尔贝塔基因的胚系变异与癌症有关的假设。出于这些目的，我们将描述自发和诱发的肿瘤发生和突变的特征。我们最近发现了Pol beta的结肠癌变种，第三个目标是测试这些变种与癌症有关的假设。我们将使用焦点形成和锚定独立生长试验来表征细胞转化。基因组不稳定性将使用CII和染色体畸变分析进行评估。这些研究的意义在于了解BER作为一种肿瘤抑制机制的作用。 公共卫生相关性：这项应用的目标是确定在人及其肿瘤中发现的DNA聚合酶β基因变异如何与癌症有关。这一点很重要，因为它有可能为癌症是如何发生和发展的，以及它如何对各种癌症治疗产生抗药性提供见解。

DESCRIPTION (provided by applicant): Polymerase Beta Variants and Cancer. Abstract: DNA polymerase beta functions in base excision repair (BER) which is important for the repair of endogenous DNA damage and damage caused by agents such as ionizing radiation. The broad long-term objective of the proposed research is to understand how aberrant BER is linked to carcinogenesis and the treatment of cancer with agents including ionizing radiation. The application consists of three specific aims. The first aim is to test the hypothesis that a cancer-associated variant of Pol beta induces tumorigenesis in mice. The second aim is to test the hypothesis that a germline variant of Pol beta is linked to cancer. For these aims we will characterize spontaneous and induced tumorigenesis and mutagenesis. We have recently identified colon tumor variants of Pol beta and the third aim is to test the hypothesis that these variants are linked to cancer. We will employ the focus formation and anchorage independent growth assays to characterize cellular transformation. Genomic instability will be assessed using the cII and chromosomal aberration assays. The significance of these studies lies in understanding the role of BER as a tumor suppressor mechanism. PUBLIC HEALTH RELEVANCE: The goal of this application is to determine how variants of the DNA polymerase beta gene found in people and their tumors are linked to cancer. This is important because it has the potential to provide insights into how cancer is initiated and progresses and how it becomes resistant to various cancer therapies.