Ins and Outs of Abscission Checkpoint Signaling: Molecular Mechanisms Safeguarding Abscission

脱落检查点信号的来龙去脉：保护脱落的分子机制

• 批准号: 10710793
• 负责人: DAWN WENZEL
• 金额: $ 39万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10710793
• 关键词: Address; Autophagocytosis; Biological Assay; Cell Cycle Checkpoint; Cell Proliferation; Cells; Chromosomal Breaks; Chromosome Segregation; Coupled; DNA; DNA Damage; DNA biosynthesis; Development; Diagnosis; Disease; Ensure; Event; Excision; Link; Maintenance; Malignant Neoplasms; Metabolic; Mitosis; Mitotic; Molecular; Nuclear Pore; Pathway interactions; Post-Translational Protein Processing; Proteins; Regulation; Research; Signal Pathway; Signal Transduction; Structure; Therapeutic; Work; cancer cell; daughter cell; glucose metabolism; innovation; insight; interdisciplinary approach; micronucleus; novel; physical separation; premature; programs; recruit

PROJECT SUMMARY: Cytokinetic abscission is the physical separation of daughter cells that concludes mitosis. Premature abscission in the presence of incompletely segregated chromosomes can result in chromosome breaks that give rise to DNA damage and micronuclei which are hallmarks of cancer. To ensure that the onset of cytokinetic abscission is synchronized with the completion of upstream mitotic events, cells have evolved a cell cycle checkpoint known as the abscission checkpoint. Cells arrest abscission in the presence of mitotic errors such as trapped DNA in the intercellular bridge, mis formed nuclear pores, under-replicated DNA, and tension at the intercellular bridge. In this proposal we take an innovative multidisciplinary approach that combines structure function studies with cell-based assays to address major outstanding questions underlying abscission checkpoint regulation, including how cells sense checkpoint triggers, and how protective activities are coupled with abscission. In Focus 1, we will use a structure-function approach to understand the mechanism whereby the ESCRT abscission machinery recruits and triggers novel cellular autophagy pathways. In Focus 2 we will examine how the metabolic status of a cell can lead to post-translational modification of abscission checkpoint proteins to alter the fidelity of abscission, providing the first direct links between glucose metabolism and abscission checkpoint function. Taken together, this work will provide essential mechanistic, molecular-level insight into how cells promote faithful abscission, how the mistakes in abscission can lead to the development of cancer, and ultimately, suggest therapeutic strategies for combatting cancer cell proliferation.

项目概要： 细胞动力学分裂是子细胞的物理分离，从而结束有丝分裂。过早放弃 在存在不完全分离的染色体的情况下，可能导致染色体断裂， DNA损伤和微核是癌症的标志。为了确保细胞动力学分裂的开始 与上游有丝分裂事件的完成同步，细胞已经进化出已知的细胞周期检查点， 作为任务检查点细胞在有丝分裂错误的存在下阻止分裂，如在有丝分裂错误中捕获的DNA。 细胞间桥、错误形成的核孔、复制不足的DNA和细胞间桥的张力。 在这项提案中，我们采取了一种创新的多学科方法，将结构功能研究与 基于细胞的检测，以解决主要的悬而未决的问题，基本的免疫检查点调节，包括 细胞如何感知检查点触发，以及保护性活动如何与释放相结合。焦点1，我们 我将使用结构-功能的方法来理解ESCRT的机制， 招募并触发新的细胞自噬途径。在焦点2中，我们将研究 细胞可以导致解离检查点蛋白的翻译后修饰， 在葡萄糖代谢和糖化检查点功能之间提供了第一个直接联系。 总之，这项工作将提供必要的机制，分子水平的洞察细胞如何促进 忠实的放弃，放弃中的错误如何导致癌症的发展，并最终建议 用于对抗癌细胞增殖的治疗策略。