Excision of Environmental Carcinogen-DNA Lesions by Human NER enzymes

许多不同的实验表明，人类核苷酸切除修复(NER)装置 首先区分由反应产生的巨大损伤引起的结构DNA扰动 进入人体的具有代谢活性的环境致癌物质。这一步需要形成 部分打开病变部位附近的双链的XPC/HR23B复合体。最初的结构性扭曲 由损伤和随后的链分离引起的表明碱基堆积和氢 在这些最初的现象中，键的相互作用首先被削弱，然后被打破。在这个项目中，我们将 检查不同加合物构象的不同结构损伤对这些初始结构的影响 然后使用碱基序列上下文中的变化作为调整这些碱基堆积的工具 因此，我们将深入了解影响人类NER活动的具体结构因素。具体而言 目的1.人类NER装置识别和处理DNA损伤的结构基础将是 调查过了。这一目标将集中在不同化学结构、物理大小和 在其他完全相同的序列环境中位于相同位置的构象性质。在……里面 特定目标2，由损伤引起的局部DNA扭曲将通过改变碱基来调节 病变嵌入其中的序列上下文，并确定不同侧翼碱基对 NER活性的结构特征和变化。在具体目标3中，加合物结构和 识别人类NER损伤的XPC/HR23B结合碱基序列和螺旋打开模式 将研究异二聚体双链。这个项目的结果将具有最终的翻译认同感 通过提供有关耐dna修复的dna lesiosn的新信息，从而提供了重要的 关于人类人群暴露于环境致癌物质的生物标志物的信息。

It is evident from many different experiments, that the human nucleotide excision repair (NER) apparatus first distinguishes structural DNA perturbations caused by bulky lesions derived from the reactions of metabolically activated environmental carcinogens that enter the human body. This step entails the formation of XPC/HR23B complexes that partially open the duplex near the lesion site. The initial structural distortions caused by the lesions and the subsequent strand separation suggest that base-base stacking and hydrogen bonding interactions are first weakened and then broken during these initial phenomena. In this project, we will examine the effects of structurally different lesions of different adduct conformations on these initial structural distortions, and then use variations in base sequence context as a tool to modulate these base stacking interactions and thus gain insight into the specific structural factors that affect human NER activity. In Specific Aim 1, the Structural basis of recognition and processing of DNA damage by the human NER apparatus will be investigated. This aim will be focused on DNA lesions of different chemical structure, physical size, and conformational properties positioned at the same site in otherwise completely identical sequence contexts. In Specific Aim 2, the local DNA distortions caused by the lesions will be modulated by varying the base sequence context in which the lesions are embedded, and determine effects of different flanking bases on the structural characteristics and changes in NER activity. In Specific aim 3, the effects of adduct structure and base sequence on binding and patterns of helix opening by the human NER lesion-recognizing XPC/HR23B heterodimer duplex will be investigated. The results of this project will have ultimate translational identification by providing new information about DNA lesiosn that are resistant to DNA repair, thus providing important information about biomarkers of exposure of the human population to environmental carcinogens.