动粒-微管动力学和染色体震荡的分子调控。
Molecular control of kinetochore-microtubule dynamics and chromosome oscillations.
机构信息
Institute of Biochemistry, Eidgenössische Technische Hochschule (ETH) Zurich, CH-8093 Zurich, Switzerland.
出版信息
Nat Cell Biol. 2010 Apr;12(4):319-29. doi: 10.1038/ncb2033. Epub 2010 Mar 14.
Chromosome segregation in metazoans requires the alignment of sister kinetochores on the metaphase plate. During chromosome alignment, bioriented kinetochores move chromosomes by regulating the plus-end dynamics of the attached microtubules. The bundles of kinetochore-bound microtubules alternate between growth and shrinkage, leading to regular oscillations along the spindle axis. However, the molecular mechanisms that coordinate microtubule plus-end dynamics remain unknown. Here we show that centromere protein (CENP)-H, a subunit of the CENP-A nucleosome-associated and CENP-A distal complexes (CENP-A NAC/CAD), is essential for this coordination, because kinetochores lacking CENP-H establish bioriented attachments but fail to generate regular oscillations, as a result of an uncontrolled rate of microtubule plus-end turnover. These alterations lead to rapid erratic movements that disrupt metaphase plate organization. We also show that the abundance of the CENP-A NAC/CAD subunits CENP-H and CENP-I dynamically change on individual sister kinetochores in vivo, because they preferentially bind the sister kinetochore attached to growing microtubules, and that one other subunit, CENP-Q, binds microtubules in vitro. We therefore propose that CENP-A NAC/CAD is a direct regulator of kinetochore-microtubule dynamics, which physically links centromeric DNA to microtubule plus ends.
真核生物的染色体分离需要姐妹动粒在中期板上对齐。在染色体对齐过程中,双定向动粒通过调节附着微管的正极动力学来移动染色体。动粒结合微管的束在生长和收缩之间交替,导致沿纺锤体轴的规则振荡。然而,协调微管正极动力学的分子机制尚不清楚。在这里,我们表明着丝粒蛋白(CENP)-H 是 CENP-A 核小体相关和 CENP-A 远端复合物(CENP-A NAC/CAD)的一个亚基,对于这种协调至关重要,因为缺乏 CENP-H 的动粒建立了双定向附着,但由于微管正极周转率不受控制,无法产生规则的振荡。这些改变导致快速的不稳定运动,破坏了中期板的组织。我们还表明,在体内,CENP-A NAC/CAD 亚基 CENP-H 和 CENP-I 的丰度在单个姐妹动粒上动态变化,因为它们优先结合附着在生长微管上的姐妹动粒,另一个亚基 CENP-Q 在体外结合微管。因此,我们提出 CENP-A NAC/CAD 是动粒微管动力学的直接调节剂,它将着丝粒 DNA 与微管正极末端物理连接。