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How a sun protection complex moonlights in proteolysis

防晒复合物如何参与蛋白质水解

基本信息

批准号：
9353431
负责人：
HAI RAO
金额：
$ 29.91万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9353431
关键词：
Area Binding Biochemical Biochemistry Biological Biological Assay Biological Process Biophysics Cells Cellular biology Cockayne Syndrome Complex Coupling DNA Damage DNA Repair DNA Repair Disorder DNA lesion Defect Degradation Pathway Disease Drug Targeting Exhibits Future Genetic Genome Scan Genomics Goals Health Hereditary Disease Homologous Gene Human In Vitro Intervention Knowledge Lead Light MDM2 gene Mammalian Cell Mediating Molecular Molecular Biology Molecular Target Multiple Myeloma Mutation Nature Nucleotide Excision Repair Pathogenicity Pathway interactions Patients Phenotype Physiological Play Process Proteasome Inhibitor Protein p53 Proteins Proteolysis Proteomics Regulation Role Saccharomyces cerevisiae Skin Cancer Solid Substrate Specificity Sun Exposure Sunlight System TP53 gene Therapeutic Ubiquitin Ubiquitin-mediated Proteolysis Pathway Work Xeroderma Pigmentosum Yeasts cofactor disease phenotype foot human disease in vitro Assay in vivo insight interdisciplinary approach multicatalytic endopeptidase complex new therapeutic target novel novel strategies novel therapeutic intervention protein degradation public health relevance repaired response sun protection targeted treatment tool ubiquitin ligase ultraviolet irradiation yeast protein

项目摘要

DESCRIPTION (provided by applicant): Our long-term goal is to understand the mechanism and function of the ubiquitin- proteasome system in health and disease. This proposal focuses on the function of the XPC-Rad23 complex in DNA damage response and proteolysis. Mutations in XPC protein lead to a genetic disorder Xeroderma pigmentosum (XP) that exhibits extreme sunlight sensitivity and a strong propensity for skin cancer. XPC was known previously as a key DNA repair factor that cells employ to protect from sunlight-inflicted DNA injury. Specifically, XPC forms a complex with Rad23 and together scan the genome for DNA lesions, which can trigger nucleotide excision repair. However, not all of the phenotypes in XPC patients can be easily explained by DNA repair defects, suggesting that XPC may have other cellular roles. Others and we have previously found that its cofactor Rad23 participates in ubiquitin-mediated proteolysis. Rad23 specifically promotes the transfer of ubiquitylated substrates to the proteasome, which remains one of the most challenging issues in the ubiquitin field. Why do cells employ the same XPC-Rad23 complex in two distinct processes: DNA repair and proteolysis? We hypothesize that XPC and Rad23 functionally coordinate proteolysis and DNA damage response, and XPC mechanistically assists Rad23 in substrate selection. We have carved out unique niches and established solid footings to unravel the detailed mechanisms underlying the biological function of Rad23 and XPC in yeast and mammalian cells. We will tackle the elusive mechanism governing the dual role of XPC and Rad23 in proteolysis and DNA damage response via various state-of-art approaches including molecular biology, biochemistry, biophysics, genomics and proteomics. We propose the following aims in an effort to decipher the biological role of the XPC-Rad23 complex in substrate proteolysis. Aim 1 is to define the physiological role of Rad23 and XPC in mammalian cells. Aim 2 is to determine the biological function of Rad23 and Rad4 (yeast counterpart of XPC) in yeast. These studies should reveal novel insights into the mechanisms and functions of the ubiquitin system in DNA damage response. As ubiquitin plays pivotal regulatory functions in nearly every area of cell biology, the results will strongly impact other biological studies and provide defined molecular targets for future intervention in human diseases.

描述(由申请人提供)：我们的长期目标是了解泛素-蛋白酶体系统在健康和疾病中的机制和功能。本研究的重点是XPC-RAD23复合体在DNA损伤反应和蛋白质降解中的作用。XPC蛋白的突变导致一种遗传性疾病着色性干皮病(XP)，这种疾病表现出对阳光极端敏感和患皮肤癌的强烈倾向。XPC以前被认为是一个关键的DNA修复因子，细胞利用它来保护细胞免受阳光造成的DNA损伤。具体地说，XPC与RAD23形成复合体，共同扫描基因组中的DNA损伤，这可以引发核苷酸切除修复。然而，并不是XPC患者的所有表型都可以很容易地用DNA修复缺陷来解释，这表明XPC可能具有其他细胞作用。其他的，我们已经发现它的辅助因子RAD23参与了泛素介导的蛋白分解。RAD23特别促进泛素化底物向蛋白酶体的转移，这仍然是泛素领域最具挑战性的问题之一。为什么细胞在两个不同的过程中使用相同的XPC-RAD23复合体：DNA修复和蛋白质分解？我们假设XPC和RAD23在功能上协调蛋白质降解和DNA损伤反应，而XPC在机械上帮助RAD23选择底物。我们开辟了独特的生态位，并建立了坚实的基础，以揭开RAD23和XPC在酵母和哺乳动物细胞中生物学功能的详细机制。我们将通过包括分子生物学、生物化学、生物物理学、基因组学和蛋白质组学在内的各种最先进的方法来解决XPC和RAD23在蛋白质降解和DNA损伤反应中双重作用的难以捉摸的机制。我们提出以下目标，以努力破译XPC-RAD23复合体在底物蛋白降解中的生物学作用。目的1确定RAD23和XPC在哺乳动物细胞中的生理作用。目的2确定RAD23和RAD4(XPC的酵母对应物)在酵母中的生物学功能。这些研究将揭示泛素系统在DNA损伤反应中的机制和功能。由于泛素在细胞生物学的几乎每个领域都发挥着关键的调节功能，其结果将强烈影响其他生物学研究，并为未来干预人类疾病提供明确的分子靶点。