Arylamine DNA adduct recognition in eukaryotic nucleotide excision repair

真核核苷酸切除修复中芳胺 DNA 加合物识别

• 批准号: 9372223
• 负责人: Bongsup P Cho
• 金额: $ 20.92万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9372223
• 关键词: 4-biphenylamine; Americas; Aromatic Amines; Binding; Binding Proteins; Cells; Characteristics; Chemicals; Chemotherapy-Oncologic Procedure; Collaborations; Communication; Complex; DNA; DNA Adducts; DNA Damage; DNA lesion; DNA-Protein Interaction; Differential Scanning Calorimetry; Dissociation; Environmental Pollution; Environmental Risk Factor; Etiology; Eukaryota; Exhibits; Exposure to; Fluorescence Spectroscopy; Human; Human Genome; Impairment; Kinetics; Knowledge; Lead; Lesion; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Microscopy; Modeling; Molecular; Molecular Conformation; Mono-S; Mutation; Nature; Nucleotide Excision Repair; Nucleotides; Orthologous Gene; Pathologic; Pathway interactions; Photosensitivity; Play; Predisposition; Principal Investigator; Process; Proteins; RAD23B gene; Recruitment Activity; Repair Complex; Research; Resistance; Resolution; Risk; Role; Site; Skin Cancer; Structure; Sunlight; Surface Plasmon Resonance; Thermodynamics; Time; United States National Academy of Sciences; X-Ray Crystallography; Xeroderma Pigmentosum; Yeasts; adduct; analog; assault; base; cancer cell; citrate carrier; combat; environmental chemical; environmental mutagens; gene repair; genome integrity; genome-wide; genotoxicity; interdisciplinary approach; killings; men; molecular imaging; novel; novel strategies; programs; protein complex; protein structure; public health relevance; repaired; single molecule; three dimensional structure; time use; tumorigenesis

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

项目负责人/主要研究者（最后一名、第一名、中间名）：Cho，Bongsup P. 项目总结/摘要 人类基因组不断受到环境因素的攻击，包括阳光和化学物质。 芳香胺是一种广泛存在的环境致突变剂，与各种散发性 癌的直接接触芳胺，如4-氨基联苯，会增加膀胱癌的风险， 美国男性第四常见的癌症吸收到细胞中的芳胺被激活并与 细胞DNA产生大体积的DNA加合物。如果不能有效修复，这些病变可能导致突变 和肿瘤发生。核苷酸切除修复（NER）是保护细胞完整性的关键修复途径。 基因组对不同的DNA损伤，包括芳胺加合物。为了启动NER， 色素C（XPC）蛋白复合物首先检测病变并招募下游因子， 验证、切除和修复DNA的受损部分。虽然人们普遍认为稳定， 有效的修复需要与XPC特异性结合，但我们最近发现这并不总是正确的：对于某些 在高度致突变序列背景下的芳胺损伤，与XPC的极紧密结合（由于缓慢的 解离速率）事实上可能妨碍NER（希尔顿等人，PLos One e0157784（2016））。这项建议旨在 研究XPC结合之间这种有趣关系的结构和机制基础， 和芳香胺损伤的修复潜力。我们将使用一种强大的多学科方法， 19 F-NMR、表面等离子体共振（SPR）和X射线晶体学的互补强度。的 关于某些病变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 对抗癌症的新想法和药剂。 OMB编号0925-0001/0002（2012年8月批准至2015年8月31日修订版）页码续页格式页码