1/13/2024 0 Comments Mitotic spindleMore likely due to too large in molecular weight and too complicated in molecular features, the underlying mechanisms for functions of NuMA remain largely mysterious so far. NuMA molecule is roughly divided into a globular head, a tail domain, and a discontinuous coiled-coil middle domain with 1500 amino acid residues 20, 21. NuMA is phosphorylated by the mitotic kinases Aurora A and cyclin-dependent kinase-1 during mitosis 17, 18, 19, through which its balanced dynamic localization and function on the spindle pole and the cell cortex are tightly regulated. In addition to its spindle pole localization and function in organization of the spindle poles, NuMA is also recruited to cell cortex in complex with dynein–dynactin by LGN 15, where it regulates spindle orientation through forming dynein–dynactin–NuMA clusters at the mitotic cell cortex 16. It concentrates at the mitotic spindle poles controversially dependent on dynein proteins 12, 13, and depletion of NuMA or dynein may result in focus defects of the mitotic spindle poles 13, 14. NuMA ( Nuclear Mitotic Apparatus) is a large spindle microtubule-associated protein that plays a dual role in organizing the mitotic spindle poles and controlling the spindle orientation in mitosis. Nevertheless, although plenty of efforts have been paid, the underlying mechanisms for the mitotic spindle assembly, structural dynamics, and accurate function are still poorly understood. Among the Kinesin-13 family members, Kif2A is concentrated mainly at the spindle poles and regulates the poleward spindle microtubule flux through depolymerizing the microtubules at their minus end during chromosome congression and segregation 8, 9, 10, 11. Kinesin-13 family members are responsible for depolymerization of microtubules and provide important ways to regulate the spindle assembly and structural dynamics. The mitotic spindle assembly and structural dynamics are regulated by a variety of complicated mechanisms, among which the poleward spindle microtubule flux has been proposed to control the dynamic spindle length and structure maintenance via continuously adding tubulin subunits at the plus end of the spindle microtubule and flowing them to the minus end where they are removed 3, 5, 6, 7, 8, 9. The mitotic spindle directly regulates accurate chromosome congression and segregation through correct connection with kinetochores assembled on both sites of each chromosome in mitosis and failure to do so may result in chromosome instability and abnormal cell division, leading to cell death or malignant cell proliferation 1, 2, 3, 4. In this work, we show that NuMA orchestrates mitotic spindle assembly, structural dynamics and function via liquid-liquid phase separation regulated by Aurora A phosphorylation.Ī well-assembled mitotic spindle is a dynamic macromolecular structure in which microtubules, microtubule-associated, and motor proteins tightly cooperate for its assembly, structural dynamics, and function. Phase-separated NuMA droplets concentrate tubulins, bind microtubules, and enrich crucial regulators, including Kif2A, at the spindle poles, which then depolymerizes spindle microtubules and promotes poleward spindle microtubule flux for spindle assembly and structural dynamics. Phase separation of NuMA is mediated by its C-terminus, whereas its dynein-dynactin binding motif also facilitates this process. NuMA undergoes liquid-liquid phase separation during mitotic entry and KifC1 facilitates NuMA condensates concentrating on spindle poles. Here we show that NuMA regulates this assembly process via phase separation regulated by Aurora A. A functional mitotic spindle is essential for accurate chromosome congression and segregation during cell proliferation however, the underlying mechanisms of its assembly remain unclear.
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