DNA polymerase iota as a putative tumor suppressor

描述(由申请人提供)：最近的进展涉及容易出错的DNA聚合酶在高等真核细胞中由环境致癌物诱导的几乎所有突变的产生。这些数据支持了基于选择性调节这些蛋白质的活性的癌症化学预防的前景，其基础是减少突变频率将降低癌症的发病率。然而，使用这些聚合酶中的一种或另一种缺乏的新开发的小鼠模型进行的致癌研究产生了意想不到的结果。具体地说，这种被称为DNA聚合酶IOTA(Poliota)的聚合酶的缺失导致内源性报告基因在紫外线(UV)照射下的突变频率大大降低。这些结果将预测对紫外线致癌作用的保护作用。然而，Poliota基因缺陷的动物表现出侵袭性皮肤癌的高度加速发展。这一意想不到的结果与癌症发生的体细胞突变假说不一致，并突显了这样一个事实，即我们对这一聚合酶宇宙的细胞功能的了解存在关键差距。这项申请建议检查Poliota可能的肿瘤抑制功能，并直接响应当前的计划公告，因为调节这一途径中的酶的活性已被提议作为一种潜在的抗突变策略。这一应用解决了DNA聚合酶IOTA作为肿瘤抑制因子的总体假设，其机制与其作为容易出错的聚合酶的活性不同。为了审查这一点，我们提出了一个试点项目，该项目将包括两个具体目标。在目标1中，我们建议研究聚合酶缺乏症对紫外线诱导的基因表达变化和损伤诱导的小鼠和人类细胞周期检查点的影响。在目标2中，我们将使用新的小鼠模型来研究紫外线致癌研究中聚合酶iota缺乏的影响。这项应用将填补我们关于癌症是如何由最普遍的环境致癌物质引发的知识的关键空白。这项研究的最终目标是了解致癌物是如何导致癌症的，以便设计预防这种疾病的策略。

DESCRIPTION (provided by applicant): Recent advances implicate error-prone DNA polymerases in the generation of virtually all mutations induced by environmental carcinogens in higher eukaryotic cells. These data have supported the promise of cancer chemoprevention based on the selective modulation of the activity of these proteins, based on the assumption that reducing the mutant frequency will reduce the incidence of cancer. However, carcinogenesis studies using newly-developed mouse models in which one or another of these polymerases is deficient have yielded unexpected results. Specifically, the deficiency of one such polymerase, termed DNA polymerase iota (pol iota), resulted in greatly decreased mutation frequencies induced by ultraviolet (UV) radiation in an endogenous reporter gene. These results would predict a protective effect against the carcinogenic effects of UV. However, pol iota-deficient animals exhibited a highly accelerated development of aggressive skin cancer. This unexpected result is not consistent with the somatic mutation hypothesis of carcinogenesis, and highlights the fact that there are critical gaps in our knowledge of the cellular function of this universe of polymerases. This application proposes to examine the putative tumor suppressor function of pol iota, and is directly responsive to the current Program Announcement since modulation of the activity of enzymes in this pathway has been proposed as a potential antimutator strategy. This application addresses the overall hypothesis that DNA polymerase iota acts as a tumor suppressor by a mechanism that is distinct from its activity as an error-prone polymerase. To examine this, we propose a pilot project that will consist of two Specific Aims. In Aim 1, we propose to examine the effect of polymerase iota deficiency on UV-induced changes in gene expression and on damage-induced cell cycle checkpoints in murine and human cells. In Aim 2, we will examine the effect of polymerase iota deficiency in UV carcinogenesis studies that employ novel murine models. This application will fill critical gaps in our knowledge of how cancer is initiated by the most ubiquitous environmental carcinogen. The ultimate goal of this research is to understand how carcinogens cause cancer in order to design strategies to prevent the disease.