Nishino Michiya, Kurasawa Yasuhiro, Evans Randall, Lin Sue-Hwa, Brinkley Bill R, Yu-Lee Li-Yuan
Program in Cell and Molecular Biology, Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA.
Curr Biol. 2006 Jul 25;16(14):1414-21. doi: 10.1016/j.cub.2006.05.052.
The equal distribution of chromosomes during mitosis is critical for maintaining the integrity of the genome. Essential to this process are the capture of spindle microtubules by kinetochores and the congression of chromosomes to the metaphase plate . Polo-like kinase 1 (Plk1) is a mitotic kinase that has been implicated in microtubule-kinetochore attachment, tension generation at kinetochores, tension-responsive signal transduction, and chromosome congression . The tension-sensitive substrates of Plk1 at the kinetochore are unknown. Here, we demonstrate that human Nuclear distribution protein C (NudC), a 42 kDa protein initially identified in Aspergillus nidulans and shown to be phosphorylated by Plk1 , plays a significant role in regulating kinetochore function. Plk1-phosphorylated NudC colocalizes with Plk1 at the outer plate of the kinetochore. Depletion of NudC reduced end-on microtubule attachments at kinetochores and resulted in defects in chromosome congression at the metaphase plate. Importantly, NudC-deficient cells exhibited mislocalization of Plk1 and the Kinesin-7 motor CENP-E from prometaphase kinetochores. Ectopic expression of wild-type NudC, but not NudC containing mutations in the Plk1 phosphorylation sites, recovered Plk1 localization at the kinetochore and rescued chromosome congression. Thus, NudC functions as both a substrate and a spatial regulator of Plk1 at the kinetochore to promote chromosome congression.
有丝分裂过程中染色体的均匀分配对于维持基因组的完整性至关重要。这一过程的关键在于动粒对纺锤体微管的捕获以及染色体向中期板的汇聚。Polo样激酶1(Plk1)是一种有丝分裂激酶,与微管-动粒附着、动粒处张力的产生、张力响应信号转导以及染色体汇聚有关。Plk1在动粒处的张力敏感底物尚不清楚。在此,我们证明人类核分布蛋白C(NudC),一种最初在构巢曲霉中发现且显示可被Plk1磷酸化的42 kDa蛋白,在调节动粒功能中起重要作用。Plk1磷酸化的NudC与Plk1在动粒的外板共定位。NudC的缺失减少了动粒处微管的端对端附着,并导致中期板处染色体汇聚缺陷。重要的是,缺乏NudC的细胞在前期动粒处表现出Plk1和驱动蛋白-7马达蛋白CENP-E的定位错误。野生型NudC的异位表达,而非在Plk1磷酸化位点含有突变的NudC,恢复了Plk1在动粒处的定位并挽救了染色体汇聚。因此,NudC在动粒处作为Plk1的底物和空间调节因子发挥作用,以促进染色体汇聚。