Excision of Environmental Carcinogen-DNA Lesions by Human NER enzymes

从许多不同的实验中可以明显看出，人类核苷酸切除修复（NER）装置 首先区分结构DNA扰动所造成的庞大的病变来源于反应， 代谢活化的环境致癌物进入人体。这一步需要形成 XPC/HR 23 B复合物的部分打开病变部位附近的双链体。最初的结构性扭曲 由损伤和随后的链分离引起的碱基-碱基堆积和氢 在这些初始现象中，键合相互作用首先被削弱，然后被破坏。在这个项目中，我们将 检查不同加合物构象的结构不同损伤对这些初始结构的影响， 扭曲，然后使用碱基序列背景中的变化作为工具来调节这些碱基堆积 研究人员通过分析它们之间的相互作用，从而深入了解影响人类NER活动的特定结构因素。在特定 目的1、研究人NER装置识别和处理DNA损伤的结构基础， 研究了这一目标将集中在不同化学结构、物理大小和 在其他方面完全相同的序列背景中，位于相同位点的构象性质。在 具体目标2，由病变引起的局部DNA畸变将通过改变碱基来调节 序列背景，其中病变嵌入，并确定不同的侧翼碱基的影响， 净入学率活动的结构特点和变化。在具体目标3中，研究了加合物结构和 识别人NER损伤的XPC/HR 23 B结合的碱基序列和螺旋打开模式 将研究异二聚体双链体。这个项目的结果将有最终的翻译鉴定 通过提供关于抵抗DNA修复的DNA损伤的新信息，从而提供重要的 关于人类暴露于环境致癌物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.