Defining the mechanisms by which NuMA drives spindle mechanical robustness

定义 NuMA 驱动主轴机械稳健性的机制

基本信息

  • 批准号:
    10677401
  • 负责人:
  • 金额:
    $ 4.36万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-12-01 至 2025-11-30
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract Errors in chromosome segregation lead to aneuploidy, a hallmark of cancer where daughter cells have extra or missing chromosome copies. Spindle pole defects, such as multipolarity, are one cause of aneuploidy, indicating that pole integrity is critical to segregation fidelity. Thus, understanding how the spindle’s mechanical robustness emerges to build and maintain proper poles is crucial to understanding how the spindle accurately functions, and how it fails in disease such as cancer. The protein NuMA and the motor dynein drive pole focusing by clustering microtubule minus-ends. Given this role in pole focusing, altering NuMA expression or function could lead to cancer by increasing multipolarity and aneuploidy. Indeed, NuMA is overexpressed in certain cancer types and NuMA overexpression correlates with increased multipolarity and aneuploidy. However, the molecular mechanisms by which NuMA gives rise to spindle mechanics and pole integrity, and its role in cancer, are far from clear. Based on recent work and preliminary data, I hypothesize that NuMA plays two separate roles in spindle mechanics and that NuMA disruptions in cancer cells affect both roles: a passive (non-energy consuming) role crosslinking microtubules and a role regulating the motility of the active motor dynein. Either or both roles could be disrupted, and targeted, in a cancer context. Here, I propose to test this hypothesis by combining molecular and mechanical perturbations, microscopy, and quantitative image analysis in human metaphase cells. In Aim 1, I will test whether and how NuMA plays a dynein-independent, passive role in spindle mechanics. To do so, I will use PDMS-based cell confinement to mechanically challenge normal and cancer spindles where NuMA can and cannot interact with dynein, and will compare how poles structurally fail under force. In Aim 2, I will determine how NuMA regulates dynein function to drive spindle mechanics. Using a functional NuMA/dynein transport assay, I will test whether and how NuMA regulates dynein force generation in the spindle. Specifically, I will compare the ability of different NuMA mutants to change dynein force generation, focusing on a mutant that lacks the coiled-coil suspected necessary for dynein activation and a mutant preventing NuMA from oligomerizing and clustering dyneins together. Finally, I will use these same NuMA mutants and cell confinement to test if NuMA regulating dynein is essential for pole mechanical integrity in cancer spindles. Together, these aims will determine how the essential protein NuMA drives spindle mechanics and how NuMA’s active and passive roles contribute to its disrupted function in cancer cells. As such, this work will allow us to identify mechanisms for spindle pole failures and may provide new therapeutic strategies to control multipolarity and aneuploidy in cancer.
项目总结/文摘

项目成果

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Nathan Cho其他文献

Nathan Cho的其他文献

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