DNA Polymerase Beta Variants and Cancer

描述（由申请人提供）：聚合酶 Beta 变体和癌症。摘要：DNA聚合酶β在碱基切除修复（BER）中发挥作用，这对于修复内源性DNA损伤和电离辐射等物质引起的损伤非常重要。拟议研究的广泛长期目标是了解异常 BER 如何与癌发生以及使用电离辐射等药物治疗癌症相关。该应用程序包含三个具体目标。第一个目的是检验 Pol beta 的癌症相关变体诱导小鼠肿瘤发生的假设。第二个目的是检验 Pol beta 的种系变异与癌症相关的假设。为了这些目的，我们将描述自发和诱导的肿瘤发生和诱变的特征。我们最近发现了 Pol beta 的结肠肿瘤变体，第三个目标是检验这些变体与癌症相关的假设。我们将采用焦点形成和锚定独立生长测定来表征细胞转化。将使用 cII 和染色体畸变测定来评估基因组不稳定性。这些研究的意义在于了解 BER 作为肿瘤抑制机制的作用。 公共健康相关性：本申请的目标是确定在人类及其肿瘤中发现的 DNA 聚合酶 β 基因变异如何与癌症相关。这很重要，因为它有可能提供有关癌症如何发生和进展以及如何对各种癌症疗法产生耐药性的见解。

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.