CHARACTERIZATION OF BASE EXCISION REPAIR VARIANTS

这项研究的广泛的长期目标是确定碱基切除修复的改变是否会影响基因表达。 (BER)存在于正常人群和肿瘤中的基因导致可能与肿瘤相关的表型。 癌症病因或治疗反应。应用程序的具体目的是检验假设 BER基因的多态性导致细胞转化，以检验BER变体 在正常人群和肿瘤中出现导致基因组不稳定性，并测试假设， BER蛋白变体影响癌症治疗。为了验证这些假设，我们将采取一个组合的遗传和 生物化学方法我们将在细胞中表达变异BER蛋白，并确定它们是否诱导 病灶形成、锚定非依赖性生长和小鼠肿瘤。我们将确定是否表达 细胞中的变异体诱导突变，并描述它们诱导的突变类型。我们将确定是否 这些变体对各种癌症治疗，包括电离辐射， 烷基化剂，后者与项目1合作。我们还将描述 与项目1、2和4合作，研究了多种DMA修复途径受损的细胞。这 该提案有可能进一步加深我们对BER变异与癌症之间关系的理解 病因学，并提供机制的见解异常BER在癌症发病和治疗中的作用。 因为BER每天负责每个细胞10,000个损伤的修复，是一个高度协调的 在这个过程中，我们怀疑即使是这个系统中的轻微失衡也会影响癌症病因。的透彻 对人体BER变异的了解也将作为未来环境研究的基础。 在这些BER变体的背景下，癌症促进和进展的方面，并具有潜在的 提供关于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.