Arylamine DNA adduct recognition in eukaryotic nucleotide excision repair

项目主任/首席调查员(最后、第一、中间)：Cho，Bongsup P. 项目摘要/摘要 人类基因组不断受到包括阳光和化学物质在内的环境因素的攻击。 芳香胺是一种广泛存在的环境诱变剂，与各种散发性疾病的病因有关。 癌症。直接接触芳胺，如4-氨基联苯，会增加患膀胱癌的风险 在美国男性中排名第四的常见癌症。被细胞吸收的芳胺被激活并与之反应 细胞DNA产生巨大的DNA加合物。如果不能有效地修复，这些损伤可能会导致突变 和肿瘤的发生。核苷酸切除修复(NER)是一条关键的修复途径，它保护了 抗多种DNA损伤，包括芳胺加合物。启动NER，干皮病 色素C(XPC)蛋白复合体首先检测病变并招募下游因素，进而 验证、切除和修复受损的DNA部分。虽然人们普遍认为，稳定， 有效的修复需要特定的绑定到XPC，我们最近发现这并不总是正确的：肯定的 芳胺损伤在高度诱变的序列背景下，与XPC结合非常紧密(由于缓慢的 离解率)实际上可能阻碍NER(Hilton等人，PLOS one e0157784(2016))。这项建议旨在 研究XPC-结合之间这种有趣的关系背后的结构和机制基础 以及芳胺损伤的修复潜力。我们将使用一种强大的多学科方法，将 19F-核磁共振、表面等离子激元共振(SPR)和X射线结晶学的互补优势。这个 关于某些损伤如何在与修复蛋白紧密结合的同时逃避修复的知识，也可能导致 抗击癌症的新想法和新制剂。 OMB编号0925-0001/0002(08/12版批准至2015年8月31日)页面续格式页面

Program Director/Principal Investigator (Last, First, Middle): Cho, Bongsup P. Project Summary/Abstract The human genome is under constant assault by environmental factors that include sunlight and chemicals. Arylamines are diverse and ubiquitous environmental mutagens implicated in the etiology of various sporadic cancers. Direct exposure to arylamines, such as 4-aminobiphenyl, increases the risk of bladder cancer, the fourth most common cancer in men in the US. Arylamines absorbed into the cells are activated and react with cellular DNA to produce bulky DNA adducts. If not efficiently repaired, these lesions can result in mutations and tumorigenesis. Nucleotide excision repair (NER) is a key repair pathway that protects the integrity of the genome against diverse DNA lesions including arylamine adducts. To initiate NER, the xeroderma pigmentosum C (XPC) protein complex first detects the lesions and recruits downstream factors, which in turn verify, excise and restore the damaged portion of the DNA. Though it has been generally believed that stable, specific binding to XPC is required for efficient repair, we recently found that it is not always true: for certain arylamine lesions in a highly mutagenic sequence context, an extremely tight binding to XPC (due to a slow dissociation rate) may, in fact, hamper NER (Hilton et al., PLos One e0157784 (2016)). This proposal seeks to investigate the structural and mechanistic basis underlying this intriguing relationship between the XPC-binding and repair potentials of arylamine lesions. We will use a powerful multidisciplinary approach that combines the complementary strengths of 19F-NMR, surface plasmon resonance (SPR), and X-ray crystallography. The knowledge gained on how certain lesions evade repair while tightly binding to repair proteins, may also lead to novel ideas and agents to combat cancer. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page