DNA SEARCH AND BASE FLIPPING MECHANISMS OF DNA GLYCOSYLASE, MUTM

DNA 糖基化酶 MUTM 的 DNA 搜索和碱基翻转机制

• 批准号: 7955121
• 负责人: GREGORY Lawrence VERDINE
• 金额: $ 3.64万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7955121
• 关键词: Bacterial DNA; Base Excision Repairs; Catalysis; Computer Retrieval of Information on Scientific Projects Database; DNA; DNA Damage; DNA glycosylase; Disulfides; Funding; Genome; Grant; Guanine; Institution; Lesion; Light; Pathway interactions; Proteins; Rare Lesion; Research; Research Personnel; Resources; Site; Source; United States National Institutes of Health; base; computer studies; crosslink; nucleobase; structural biology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. MutM is a bacterial DNA glycosylase that specifically recognizes oxidatively damaged DNA bases and initiates the base excision repair pathway. Given the subtle conformational differences in the lesion base, 8-oxoguanine, and normal DNA base, guanine, and the scarcity of the lesions, a fundamental question arises: how does MutM locate the rare lesion sites among the vast genome? In addition, base flipping, an essential step for DNA glycosylase catalysis, is not well understood and whether protein is actively promoting base extrusion is currently in debate. Using the disulfide crosslinking strategy, we have covalently trapped ordinarily transient intermediates during the search by MutM for lesions during nucleobase extrusion. These intermediates not only shed light on the mechanism of lesion recognition and catalysis, but have also provided valuable starting points for our computational studies of the base extrusion pathway.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 MUTM是一种细菌DNA糖基化酶，它专门识别氧化损坏的DNA碱基并启动碱基切除修复途径。 鉴于病变基碱，8-氧气和正常的DNA碱，鸟嘌呤以及病变的稀缺性的细微构象差异，因此出现了一个基本问题：MUTM如何在巨大的基因组中找到罕见的病变位点？ 此外，基本翻转是DNA糖基酶催化的重要步骤，目前尚不清楚蛋白质是否正在积极促进碱基挤出。 使用二硫键交联策略，我们在MUTM搜索核碱酶挤出过程中为病变搜索期间共价捕获了通常的短暂性中间体。 这些中间体不仅阐明了病变识别和催化的机制，而且还为我们对基础挤出途径的计算研究提供了宝贵的起点。