DNA polymerase iota as a putative tumor suppressor

描述（由申请人提供）：最近的进展表明，在高等真核细胞中，易出错的DNA聚合酶在环境致癌物诱导的几乎所有突变的产生中都有作用。这些数据支持了基于选择性调节这些蛋白质活性的癌症化学预防的前景，基于减少突变频率将减少癌症发病率的假设。然而，使用这些聚合酶中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。具体来说，一种称为DNA聚合酶iota （pol iota）的聚合酶的缺乏导致内源性报告基因在紫外线（UV）辐射诱导下突变频率大大降低。这些结果将预测对紫外线致癌作用的保护作用。然而，缺乏pol - iota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变的体细胞突变假说不一致，并突出了这样一个事实，即我们对聚合酶的细胞功能的认识存在关键空白。该应用程序旨在检测pol - iota的推定肿瘤抑制功能，并且直接响应当前的程序公告，因为该途径中酶活性的调节已被提出作为潜在的抗突变策略。该应用程序解决了DNA聚合酶iota作为肿瘤抑制因子的机制不同于其作为易出错聚合酶的活性的总体假设。为了研究这一点，我们提出了一个试点项目，该项目将包括两个具体目标。在目的1中，我们建议在小鼠和人类细胞中检测聚合酶iota缺乏对紫外线诱导的基因表达变化和损伤诱导的细胞周期检查点的影响。在目标2中，我们将采用新型小鼠模型研究聚合酶iota缺乏在紫外线致癌研究中的作用。这个应用程序将填补我们关于癌症是如何由最普遍的环境致癌物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.