POLYMORPHIC VARIANTS IN HUMAN MUTY

描述（改编自研究者摘要） 最近的研究表明，遗传多态性发生在 这些基因构成了主要的DNA修复途径。 许多人体内的突变 这些基因可导致毒性和致突变性增加。 在基座内 切除修复途径，修复的主要DNA损伤之一是 氧化损伤鸟嘌呤8-oxoG 这种病变的积累已经 与衰老、癌症、神经变性和动脉粥样硬化相关。 之一 对这种错配的有效修复至关重要的基因是 腺嘌呤特异性DNA糖基化酶MutY，可去除A：8-oxoG处的腺嘌呤 错配 人类MutY同源物hMYH已被克隆， 鉴定的多态性变体。 为了确定函数 hMYH中这些和其他多态性变体的意义， 独立实验室与多元化但互补的实验室聚集在一起 专业知识，来解决这个问题。 第一个具体目标是确定 hMYE基因中的其他多态性变体，这些研究将 在H.莫托威瑟。 样品的选择将 是那些已经被NIH预选为具有代表性的子集 美国人口。 所有16个外显子和内含子-外显子连接将被 分析了96个基因组DNA样本。 具体目标2侧重于 天然hMYH及其多态性变体结构-功能分析。 这些研究将在S.劳埃德， 根据研究者的生化和X射线晶体学 原核MutY的测定。 第三个具体目标， I的实验室。Boldogh，将确定细胞氧化的作用， 应激对hMYH的调节和细胞内定位的影响。 多态性变体不会受到不利影响， 催化，可能会损害稳定和定位。 这些目标 将采用多学科协作方法完成 利用DNA修复酶学、结构功能分析、 多态性筛选和细胞生物学。

DESCRIPTION (Adapted From the Investigator's Abstract) Recent studies have demonstrated that genetic polymorphisms occur within the genes that comprise the major DNA repair pathways. Mutations within many of these genes can lead to increased toxicity and mutagenicity. Within the base excision repair pathway, one of the primary DNA lesions that is repaired is an oxidatively damaged guanine, 8-oxoG. The accumulation of this lesion has been correlated with aging, cancer, neurodegeneration, and atherosclerosis. One of the genes that is central to the efficient repair of this mismatch is the adenine-specific DNA glycosylase, MutY, that removes adenine at A:8-oxoG mispairs. The human MutY homolog, hMYH, has been cloned and potential polymorphic variants identified. In order to determine the functional significance of these and additional polymorphic variants in hMYH, three independent laboratories have come together with diverse but complementary expertise, to address this question. The first specific aim is to identify additional polymorphic variants in the hMYE gene and these studies will be carried out in the laboratory of H. Mohrenweiser. The choice of samples will be a subset of those that have been preselected by NIH as being representative of the U.S. population. All 16 exons and intron-exon junctions will be analyzed from 96 genomic DNA samples. Specific aim 2 focuses on the structure-function analysis of native hMYH and its polymorphic variants. These studies will be guided and implemented in the laboratory of S. Lloyd, based on the investigator's biochemical and x-ray crystallographic determination of the prokaryotic MutY. The third specific aim, carried out in the laboratory of I. Boldogh, will ascertain the role that cellular oxidative stress has on the regulation and intracellular localization of hMYH. Polymorphic variants that are not affected adversely, with respect to catalysis, may be impaired in stabilization and localization. These goals will be accomplished using a multidisciplinary collaborative approach utilizing expertise in DNA repair enzymology, structure-function analysis, polymorphic screening, and cell biology.