Cellular Events Downstream of Mitotic Errors

有丝分裂错误下游的细胞事件

• 批准号: 10063880
• 负责人: KATHARINE S ULLMAN
• 金额: $ 34.31万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063880
• 关键词: Address; Affect; Anaphase; Animals; Architecture; Blood; Cell Cycle; Cell Nucleus; Cell division; Cells; Chromatin; Chromosome Cohesion; Chromosome Segregation; Chromosomes; Complex; Cytokinesis; DNA; DNA Damage; DNA biosynthesis; Disease; Endoplasmic Reticulum; Ensure; Environment; Error Sources; Event; Excision; Foundations; Frequencies; Future; Genome; Genome Stability; Genomic Instability; Genomics; Goals; Health; Homeostasis; Image; Immune signaling; Inherited; Interphase; Intestines; Knowledge; Left; Malignant Neoplasms; Membrane; Membrane Proteins; Mitosis; Mitotic; Molecular; Monitor; Nuclear; Nuclear Envelope; Nuclear Inner Membrane; Nuclear Lamina; Nuclear Pore; Nuclear Pore Complex; Nuclear Pore Complex Proteins; Nuclear Proteins; Nuclear Structure; Organ; Outcome; Pathway interactions; Play; Pore Proteins; Process; Proteins; Quality Control; Research; Research Design; Resolution; Risk; Role; S Phase; Signal Transduction; Site; Skin; Sorting - Cell Movement; Structure; Testing; Time; aurora B kinase; chromosome missegregation; daughter cell; env Gene Products; experimental study; genome integrity; innovation; insight; interdisciplinary approach; interest; novel; novel therapeutic intervention; p53-binding protein 1; preservation; recruit; regional difference; response; scaffold; seal; segregation; telophase

PROJECT SUMMARY In animal cells, nuclear structure is completely dismantled during the process of mitosis. Although chromosomes are concomitantly remodeled into compact, protective structures, various sources of error can put genome stability at risk at this time of cell division. Chromosome division itself can be a time of genome destabilizing errors, if the spindle assembly checkpoint fails to ensure that chromosome alignment is complete prior to their segregation. In some cases, events in the previous cell cycle, such as incomplete DNA replication, put the genome in jeopardy at mitosis. In other cases, mis-coordination of events in late mitosis gives rise to DNA damage. Events downstream of these potential errors thus play an integral role in maintaining genome stability. A growing body of knowledge about the rapid steps of nuclear assembly and an appreciation for the importance of genome surveillance in newly-formed nuclei provide a foundation for the proposed research designed to address how cells cope with mitotic errors. The research proposed is centered on conceptually innovative hypotheses and seeks to make novel inroads into the inter-connections between nuclear assembly, genome surveillance, and cytokinesis. Building on the new observation that the nuclear envelope at lagging chromosomes has a specific set of constituent proteins, our first aim is to define how the nuclear envelope differs at mis-segregated chromosomes, testing the hypothesis that these changes alter membrane sealing. The impact that this distinctive nuclear envelope domain has on nuclear integrity and the frequency with which mis- segregating chromosomes re-integrate into the nucleus will be determined by live-imaging. We will also interrogate the role of the kinase Aurora B in regulating regional differences at the NE of lagging chromosomes. In cases where the lagging chromosome separates from the main nucleus, our results will also lend insight into why resulting micronuclei have attributes that escalate DNA damage and instigate innate immune signaling. The second aim is focused on mechanisms involved in genome surveillance after mitosis. To gain unique perspective on this process, we will pursue the roles of Nup153 and Nup50 in targeting the DNA damage response factor 53BP1 to surveillance foci. Finally, we will determine what activates the abscission checkpoint, a regulatory event downstream of mitosis that halts the final step of cell division. Having observed a robust connection between loss of Nup153 function and the abscission checkpoint, we hypothesize that this is due to the dual roles of Nup153 in nuclear formation and genomic surveillance. More broadly, we will test the hypothesis prompted by this paradigm: that loss of nuclear integrity --and the damage to DNA that ensues-- are monitored by the abscission checkpoint and become a particularly potent signal when genome surveillance mechanisms are compromised. The results obtained will bring significant new insight into diverse mechanisms that preserve genome integrity and contribute to an integrated understanding of fundamental cell cycle regulatory mechanisms.

项目总结 在动物细胞中，核结构在有丝分裂过程中被完全摧毁。虽然染色体 伴随着被改造成紧凑的保护性结构，各种错误来源可以将基因组 在细胞分裂的这个时候，稳定性处于危险之中。染色体分裂本身可能是基因组不稳定的时期 错误，如果主轴组件检查点未能确保染色体在其 种族隔离。在某些情况下，前一个细胞周期中的事件，如DNA复制不完整，使 基因组在有丝分裂时处于危险状态。在其他情况下，有丝分裂后期事件的不协调会导致DNA的产生。 损坏。因此，这些潜在错误下游的事件在维持基因组稳定性方面发挥了不可或缺的作用。 关于核组装的快速步骤的知识越来越多，并认识到 新形成的细胞核中的基因组监测为拟议的研究提供了基础，旨在 说明细胞如何处理有丝分裂错误。提出的研究集中在概念创新上。 假设并寻求在核组装、基因组之间的相互联系方面取得新的进展 监视和胞质分裂。建立在原子核包络滞后的新观察基础上 染色体有一组特定的组成蛋白质，我们的第一个目标是定义核膜的不同之处 在错误分离的染色体上，测试这些改变改变膜密封的假设。其影响 这个独特的核包膜结构域对核完整性和错失- 分离的染色体重新整合到细胞核中将通过实时成像来确定。我们还将 询问Aurora B在调节落后染色体NE的区域差异中的作用。 在滞后染色体从主核分离的情况下，我们的结果也将有助于深入了解 为什么由此产生的微核具有加剧DNA损伤和激发先天免疫信号的属性。这个 第二个目标是关注有丝分裂后基因组监测的机制。获得独特的视角 在这个过程中，我们将继续研究Nup153和Nup50在靶向DNA损伤反应因子中的作用 53BP1呼叫监视中心。最后，我们将确定是什么激活了分离检查点，这是一种监管事件 有丝分裂的下游，停止细胞分裂的最后一步。在观察到两者之间的牢固联系之后 失去Nup153功能和脱落检查点，我们假设这是由于Nup153的双重作用 Nup153在核形成和基因组监测中的作用。更广泛地说，我们将测试由 这种模式：核完整性的丧失--以及随之而来的DNA损伤--由 脱落检查点，并成为一个特别有力的信号，当基因组监测机制 妥协了。所获得的结果将为保存各种机制带来重要的新见解 基因组的完整性，有助于对基本的细胞周期调控机制有一个完整的理解。