Vergnolle Maïlys A S, Taylor Stephen S
Faculty of Life Sciences, Michael Smith Building, Oxford Road, University of Manchester, Manchester, UK.
Curr Biol. 2007 Jul 3;17(13):1173-9. doi: 10.1016/j.cub.2007.05.077.
Cenp-F is a nuclear matrix component that localizes to kinetochores during mitosis and is then rapidly degraded after mitosis [1]. Unusually, both the localization and degradation of Cenp-F require it to be farnesylated [2]. Five studies recently demonstrated that Cenp-F is required for kinetochore-microtubule interactions and spindle checkpoint function [3-7]; however, the underlying molecular mechanisms have yet to be defined. Here, we show that Cenp-F interacts with Ndel1 and Nde1, two human NudE-related proteins implicated in regulating Lis1/Dynein motor complexes (reviewed in [8]). We show that Ndel1, Nde1, and Lis1 localize to kinetochores in a Cenp-F-dependent manner. In addition, Nde1, but not Ndel1, is required for kinetochore localization of Dynein. Accordingly, suppression of Nde1 inhibits metaphase chromosome alignment and activates the spindle checkpoint. By contrast, inhibition of Ndel1 results in malorientations that are not detected by the spindle checkpoint; Ndel1-deficient cells consequently enter anaphase in a timely manner but lagging chromosomes then manifest. A major function of Cenp-F, therefore, is to link the Ndel1/Nde1/Lis1/Dynein pathway to kinetochores. Furthermore, our data demonstrate that Ndel1 and Nde1 play distinct roles to ensure chromosome alignment and segregation.
Cenp-F是一种核基质成分，在有丝分裂期间定位于动粒，然后在有丝分裂后迅速降解[1]。不同寻常的是，Cenp-F的定位和降解都需要其进行法尼基化修饰[2]。最近有五项研究表明，Cenp-F是动粒-微管相互作用和纺锤体检查点功能所必需的[3-7]；然而，其潜在的分子机制尚未明确。在此，我们表明Cenp-F与Ndel1和Nde1相互作用，这两种人类NudE相关蛋白参与调节Lis1/动力蛋白运动复合体（综述见[8]）。我们发现Ndel1、Nde1和Lis1以Cenp-F依赖的方式定位于动粒。此外，动力蛋白的动粒定位需要Nde1而非Ndel1。因此，抑制Nde1会抑制中期染色体排列并激活纺锤体检查点。相比之下，抑制Ndel1会导致纺锤体检查点未检测到的错误定向；因此，Ndel1缺陷细胞会及时进入后期，但随后会出现滞后染色体。因此，Cenp-F的一个主要功能是将Ndel1/Nde1/Lis1/动力蛋白途径与动粒联系起来。此外，我们的数据表明Ndel1和Nde1在确保染色体排列和分离方面发挥着不同的作用。
