DNA Polymerase Beta Variants and Cancer

描述（由申请人提供）：聚合酶β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损伤和由电离辐射等物质引起的损伤很重要。拟议研究的广泛长期目标是了解异常BER如何与致癌作用和包括电离辐射在内的药物治疗癌症有关。该申请包括三个具体目标。第一个目的是检验Pol β的癌症相关变体在小鼠中诱导肿瘤发生的假设。第二个目的是检验Pol beta的生殖系变异与癌症有关的假设。为了这些目的，我们将描述自发和诱导的肿瘤发生和诱变。我们最近发现了Pol β的结肠肿瘤变体，第三个目的是检验这些变体与癌症有关的假设。我们将采用焦点形成和锚定非依赖性生长测定来表征细胞转化。将使用cII和染色体畸变试验评估基因组不稳定性。这些研究的意义在于理解BER作为肿瘤抑制机制的作用。

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.