Mechanisms of microtubule motors and chromosome segregation

项目摘要 在有丝分裂过程中，基于微管的有丝分裂纺锤体对染色体的精确分离是 这对保持基因组的完整性至关重要。有丝分裂纺锤体功能的错误导致染色体 错误分离、非整倍性和微核的形成，这些都是肿瘤细胞的标志。分子马达 驱动蛋白超家族的成员在控制细胞的运动和组织中起着重要的机械作用。 纺锤体内的染色体，包括染色体臂上力的产生， 纺锤体微管长度发生变化，微管的交联和滑动发生重叠。许多 细胞中驱动蛋白功能的分子机制仍然知之甚少。该提案寻求 填补我们对驱动蛋白在分子水平上如何发挥作用的理解的知识空白，以确保 有丝分裂染色体分离的准确性。驱动蛋白的结构如何调节它们的活动， 在细胞中的特殊作用？这些活动在空间和时间上是如何调节的？什么是分子 驱动蛋白功能的细胞类型特异性要求的基础？什么是短期和长期 异常驱动蛋白活动的后果？结合生物物理学， 定量活细胞成像和结构诱变将用于解决这些突出的问题。 从单分子到单细胞，再到组织和整个生物体， 程度.

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.