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）是细胞中毒性最大的损伤，已知对癌症有效 治疗了解ICL如何在癌症中修复将使我们能够利用这些药物， 癌症治疗，以避免治疗耐药性，并开发可用于预防的生物标志物， 过度治疗对这些药物没有反应的患者。然而，尽管在这方面进行了广泛的研究， 在这个领域，提出一个详细的假设并精确地揭示多个DNA是如何被发现的仍然具有挑战性。 修复酶和途径在ICL修复中共同起作用。该计划项目汇集了专家， DNA修复途径的各个方面，旨在解决这个难题。项目4重点关注 关键支架蛋白SLX 4。该项目的目标1将确定细胞周期的机制- 依赖性调节含SLX 4的蛋白质复合物，并研究SLX 4和MSH 2复合物 共同促进ICL修复。目标2将从机制上定义如何招募SLX 4和SLX 4 IP， DNA损伤位点并参与ICL修复。Aim 3试图揭示SLX 4与 复合物和FA途径在ICL修复中的作用，并进一步确定这些修复组分在ICL修复中的意义。 癌症治疗这些研究，连同项目1-3中建议的研究，将提供一个框架， ICL修复人类