CHARACTERIZATION OF BASE EXCISION REPAIR VARIANTS

这项拟议的研究的广泛、长期目标是确定碱基切除修复中的变化 (BER)基因存在于正常人群和肿瘤中，导致表型可能与 癌症的病因或治疗反应。应用程序的具体目标是检验假设 BER基因的多态会导致细胞转化，以检验BER变异 在正常人群和肿瘤中出现会导致基因组不稳定，并检验以下假设 BER蛋白变异会影响癌症治疗。为了检验这些假说，我们将结合基因和 生化方法。我们将在细胞中表达不同的BER蛋白，并确定它们是否会诱导 小鼠的病灶形成、非锚定生长和肿瘤。我们将确定是否表示 细胞中的变异会导致突变，并确定它们所诱导的突变的类型。我们将确定是否 这些变异体对各种癌症治疗有不同的敏感性，包括电离辐射和 烷基化试剂，后者与项目1合作。我们还将表征 与项目1、2和4合作，其中多条DMA修复路径被破坏的单元。这 该提案有可能进一步加深我们对误码率变异与癌症之间关系的理解 病因学，并提供对异常的BER在癌症发生和治疗中的作用的机械性见解。 因为BER每天负责修复每个细胞10,000个病变，并且是高度协调的 在这个过程中，我们怀疑即使这个系统中的微小失衡也会影响癌症病因学。一次彻底的 对人类误码率变异的理解也将成为未来环境研究的基础 在这些BER变异体的背景下癌症促进和进展的方面，并具有潜在的 以提供有关癌症预防的生活方式选择的重要见解。

The broad, long-term objective of the proposed research is to determine if alterations in base excision repair (BER) genes that exist in the normal population and in tumors lead to phenotypes that could be linked to the etiology of cancer or to treatment response. The specific aims of the application are to test the hypothesis that polymorphisms in BER genes lead to cellular transformation, to test the hypothesis that BER variants arising in the normal population and in tumors lead to genomic instability, and to test the hypothesis that BER protein variants affect cancer treatment. To test these hypotheses we will take a combined genetic and biochemical approach. We will express the variant BER proteins in cells and determine whether they induce focus formation, anchorage independent growth, and tumors in mice. We will determine if expression of the variants in cells induces mutations, and characterizethe types of mutations they induce. We will determine if the variants are differentially sensitive to various cancer treatments, including ionizing radiation and alkylating agents, the latter in collaboration with Project 1. We will also characterize the drug sensitivity of cells in which multiple DMA repair pathways are compromised, in collaboration with Projects 1, 2, and 4. This proposal has the potential to further our understanding of the relationship between BER variants and cancer etiology, and to provide mechanistic insights into the role of aberrant BER in cancer onset and treatment. Because BER is responsible for the repair of 10,000 lesions per cell per day and is a highly coordinated process, we suspect that even minor imbalances in this system will impact cancer etiology. A thorough understanding of BER variants in people will also serve as the basis for a future study of environmental aspects of cancer promotion and progression within the context of these BER variants and has the potential to provide important insight on lifestyle choices regarding cancer prevention.