Lee Su Hyun, Kwon Mi-Sun, Lee Taerim, Hohng Sungchul, Lee Hyunsook
Department of Biological Sciences, Institute of Molecular Biology and Genetics, Seoul National University, Korea.
Department of Physics and Astronomy, Seoul National University, Korea.
FEBS J. 2025 Aug;292(15):3910-3925. doi: 10.1111/febs.70019. Epub 2025 Feb 15.
The maintenance of genetic integrity in proliferating cells requires the coordinated regulation of DNA replication, chromosome segregation, and cytokinetic abscission. Chromosome-microtubule interactions regulate mitosis, while interactions between the actin cytoskeleton and Myosin IIA dictate cytokinetic abscission. This process, crucial for the equal distribution of the duplicated genome into two daughter cells, occurs perpendicular to the axis of chromosome segregation. However, the mechanism of how microtubule-driven mitosis and actin-associated cytokinesis are precisely coordinated remains poorly understood. This study highlights the role of KIF18A, a kinesin-like protein, in linking kinetochore-microtubule dynamics to cytokinetic axis formation. KIF18A's localization changes through the cell division cycle, from the metaphase plate during chromosome congression to the central spindle in late anaphase, and finally to the spindle midbody in telophase. KIF18A depletion leads to chromosome congression failures and anaphase onset delays. Notably, cells attempting to undergo division in the absence of KIF18A exhibited disruptions in the parallel structure of the central spindle, causing mislocalization of the centralspindlin complex, such as kinesin-like protein KIF23 (also known as MKLP1) and Rac GTPase-activating protein 1 (RACGAP1). These disruptions impair cleavage furrow establishment, causing incomplete cytokinesis and the formation of mononuclear or binucleated cells. Our findings suggest that KIF18A is crucial for coordinating chromosome congression and cytokinesis by regulating the spatial and temporal assembly of the central spindle during late anaphase.
增殖细胞中遗传完整性的维持需要DNA复制、染色体分离和胞质分裂切割的协调调控。染色体与微管的相互作用调节有丝分裂,而肌动蛋白细胞骨架和肌球蛋白IIA之间的相互作用决定胞质分裂切割。这一过程对于将复制后的基因组平均分配到两个子细胞中至关重要,发生在与染色体分离轴垂直的方向上。然而,微管驱动的有丝分裂和肌动蛋白相关的胞质分裂如何精确协调的机制仍知之甚少。本研究强调了驱动蛋白样蛋白KIF18A在将动粒-微管动力学与胞质分裂轴形成联系起来方面的作用。KIF18A的定位在细胞分裂周期中发生变化,从染色体汇聚时的中期板到后期的中央纺锤体,最后到末期的纺锤体中间体。KIF18A的缺失导致染色体汇聚失败和后期起始延迟。值得注意的是,在没有KIF18A的情况下试图进行分裂的细胞,其中央纺锤体的平行结构出现破坏,导致中央纺锤体蛋白复合体(如驱动蛋白样蛋白KIF23,也称为MKLP1和Rac GTP酶激活蛋白1,即RACGAP1)定位错误。这些破坏损害了分裂沟的形成,导致不完全胞质分裂并形成单核或双核细胞。我们的研究结果表明,KIF18A通过在后期调节中央纺锤体的时空组装,对于协调染色体汇聚和胞质分裂至关重要。