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： 细胞动力学脱落是完成有丝分裂的子细胞的物理分离。过早脱落 在存在不完全分离的染色体的情况下可能会导致染色体断裂，从而导致 DNA 损伤和微核是癌症的标志。确保细胞因子脱落的发生 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 作为分离检查点。当存在有丝分裂错误时，例如 DNA 被困在细胞中，细胞会阻止脱落。 细胞间桥、错误形成的核孔、复制不足的 DNA 以及细胞间桥的张力。 在本提案中，我们采用创新的多学科方法，将结构功能研究与 基于细胞的检测，以解决脱落检查点调节背后的主要悬而未决的问题，包括 细胞如何感知检查点触发，以及保护活动如何与脱落相结合。在焦点1中，我们 将使用结构-功能方法来理解 ESCRT 分离机制的机制 招募并触发新的细胞自噬途径。在焦点 2 中，我们将检查代谢状态如何 细胞可以导致脱落检查点蛋白的翻译后修饰，以改变 脱落，提供了葡萄糖代谢和脱落检查点功能之间的第一个直接联系。 总而言之，这项工作将为细胞如何促进 忠实的脱落，脱落的错误如何导致癌症的发展，并最终建议 对抗癌细胞增殖的治疗策略。