Project 4: Coordinating Nucleolytic Pathways During Crosslink Repair

项目 4：在交联修复过程中协调溶核途径

• 批准号: 9148677
• 负责人: Junjie Chen
• 金额: $ 35.43万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-10 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9148677
• 关键词: Address; Alpha Cell; Area; Binding; Biochemical; Biological Markers; Cell Cycle; Cell Line; Cells; Cellular biology; Complex; Complex Analysis; DNA Damage; DNA Repair; DNA Repair Enzymes; DNA Repair Pathway; Data; ERCC1 gene; Fanconi Anemia pathway; Fanconi anemia protein; Fanconi' s Anemia; Genes; Genetic; Genome; Goals; Human; Investigation; Knowledge; Lesion; MSH2 gene; MSH3 gene; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Cell; Mediating; Molecular; Mutate; Mutation; Pathway interactions; Patient-Focused Outcomes; Patients; Phase; Phosphorylation; Post-Translational Protein Processing; Process; Proteins; Recruitment Activity; Regulation; Reporting; Resistance; Role; S Phase; Sampling; Scaffolding Protein; Site; Testing; Yeasts; cancer therapy; crosslink; enzyme pathway; experimental study; genetic analysis; in vivo; insight; mutant; novel; nuclease; prevent; programs; protein E; protein complex; repair enzyme; repaired; tool; xeroderma pigmentosum group A complementing protein

PROJECT SUMMARY Interstrand crosslinks (ICLs) are the most toxic lesions in the cell and are known to be effective in cancer treatment. Understanding how ICLs are repaired in cancers will allow us to take advantage of these agents for cancer treatment, to avoid therapy resistance, and to develop biomarkers that can be used to prevent overtreatment for patients who are not responding to these agents. However, despite extensive studies in this area, it remains challenging to come up with a detailed hypothesis and reveal precisely how multiple DNA repair enzymes and pathways act together in ICL repair. This Program Project brings together experts in various aspects of DNA repair pathways and aims at addressing this difficult question. Project 4 focuses on a critical scaffold protein SLX4. Aim 1 of this project will determine the mechanisms underlying the cell cycle- dependent regulation of SLX4-containing protein complexes and investigate how SLX4 and MSH2 complexes act together to promote ICL repair. Aim 2 will define mechanistically how SLX4 and SLX4IP are recruited to DNA damage sites and participate in ICL repair. Aim 3 attempts to uncover the connection between SLX4 complex and FA pathway in ICL repair and further determine the significance of these repair components in cancer therapy. These studies, together with the ones proposed in Projects 1-3, will provide a framework of ICL repair in humans.

项目摘要 链间交联（ICL）是细胞中最有毒的病变，已知在癌症中有效 治疗。了解如何在癌症中修复ICL，这将使我们能够利用这些代理 癌症治疗，避免抗治疗，并开发可用于防止的生物标志物 过度治疗对这些药物不反应的患者。但是，尽管有广泛的研究 领域，提出一个详细的假设并确切地揭示了多个DNA的方式仍然很具有挑战性 修复酶和途径共同作用于ICL修复。该计划项目汇集了专家 DNA修复途径的各个方面，旨在解决这个困难的问题。项目4专注于 临界支架蛋白SLX4。该项目的目标1将确定细胞周期的基础机制 依赖于SLX4的蛋白质复合物的调节，并研究SLX4和MSH2复合物如何 一起行动以促进ICL维修。 AIM 2将从机械上定义SLX4和SLX4IP的招募方式 DNA损伤部位并参与ICL维修。 AIM 3尝试发现SLX4之​​间的连接 ICL修复中的复杂和FA途径，并进一步确定这些修复组件在 癌症治疗。这些研究以及项目1-3中提出的研究将提供一个框架 ICL修复人类。