Mechanisms of microtubule motors and chromosome segregation

项目总结 在有丝分裂过程中，基于微管的有丝分裂纺锤体准确地分离了染色体 对于保持基因组的完整性是必不可少的。有丝分裂纺锤体功能错误导致染色体 分离错误、非整倍体和微核的形成，这些都是肿瘤细胞的特征。分子马达 在控制运动和组织的运动和组织中起着重要的机械作用 纺锤体内的染色体，包括在染色体臂上产生的力，调节 纺锤体微管长度改变，微管的交联性和滑移性重叠。许多人 细胞内驱动蛋白功能的分子机制仍然知之甚少。这项提议旨在 填补我们在理解动链蛋白如何在分子水平上发挥作用方面的知识空白，以确保 有丝分裂染色体分离的准确性。运动蛋白的结构是如何调节它们的活动的 在细胞中扮演特殊的角色？这些活动是如何在空间和时间上受到调控的？分子是什么？ 细胞类型对激动素功能的特殊要求？什么是短期和长期的 运动蛋白活动异常的后果是什么？一种结合生物物理学、 定量活细胞成像和结构突变将被用于解决这些突出的问题 从单个分子到单个细胞，再到组织和整个生物体的生物尺度上的问题 级别。

PROJECT SUMMARY The accurate segregation of chromosomes by the microtubule-based mitotic spindle during mitosis is essential for the preservation of genomic integrity. Errors in mitotic spindle function lead to chromosome missegregation, aneuploidy, and the formation of micronuclei, all hallmarks of tumor cells. Molecular motors of the kinesin superfamily play important mechanical roles in controlling the movement and organization of chromosomes within the spindle, including the generation of forces on chromosome arms, regulation of spindle microtubule length changes, and the crosslinking and sliding of microtubule overlaps. Many of the molecular mechanisms underlying kinesin function in cells remain poorly understood. This proposal seeks to fill knowledge gaps in our understanding of how kinesins function at the molecular level to ensure the accuracy of mitotic chromosome segregation. How do the structures of kinesins tune their activities for particular roles in cells? How are these activities spatially and temporally regulated? What is the molecular basis for cell type specific requirements of kinesin function? What are the short and long-term consequences of abnormal kinesin activities? An interdisciplinary approach combining biophysics, quantitative live cell imaging, and structural mutagenesis will be employed to address these outstanding questions across biological scales from the single molecule to single cell, to tissue and whole organism levels.