Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal.
Nat Cell Biol. 2012 Feb 5;14(3):295-303. doi: 10.1038/ncb2423.
Loss of spindle-pole integrity during mitosis leads to multipolarity independent of centrosome amplification. Multipolar-spindle conformation favours incorrect kinetochore-microtubule attachments, compromising faithful chromosome segregation and daughter-cell viability. Spindle-pole organization influences and is influenced by kinetochore activity, but the molecular nature behind this critical force balance is unknown. CLASPs are microtubule-, kinetochore- and centrosome-associated proteins whose functional perturbation leads to three main spindle abnormalities: monopolarity, short spindles and multipolarity. The first two reflect a role at the kinetochore-microtubule interface through interaction with specific kinetochore partners, but how CLASPs prevent spindle multipolarity remains unclear. Here we found that human CLASPs ensure spindle-pole integrity after bipolarization in response to CENP-E- and Kid-mediated forces from misaligned chromosomes. This function is independent of end-on kinetochore-microtubule attachments and involves the recruitment of ninein to residual pericentriolar satellites. Distinctively, multipolarity arising through this mechanism often persists through anaphase. We propose that CLASPs and ninein confer spindle-pole resistance to traction forces exerted during chromosome congression, thereby preventing irreversible spindle multipolarity and aneuploidy.
在有丝分裂过程中，纺锤体两极完整性的丧失会导致中心体扩增独立的多极性。多极纺锤体构象有利于不正确的动粒微管附着，从而影响染色体的正确分离和子细胞的存活。纺锤体两极的组织会影响动粒的活性，反之亦然，但这种关键力平衡的分子本质尚不清楚。CLASPs 是微管、动粒和中心体相关的蛋白，其功能失调会导致三种主要的纺锤体异常：单极性、短纺锤体和多极性。前两种反映了它们在动粒-微管界面的作用，通过与特定的动粒伙伴相互作用，但 CLASPs 如何防止纺锤体多极性仍然不清楚。在这里，我们发现人类 CLASPs 在双极化后响应来自未对齐染色体的 CENP-E 和 Kid 介导的力，确保纺锤体两极的完整性。该功能独立于端对端的动粒-微管附着，涉及到向剩余的中心体卫星募集九蛋白。值得注意的是，通过这种机制产生的多极性通常在后期仍然存在。我们提出 CLASPs 和九蛋白赋予纺锤体两极抵抗染色体汇聚过程中产生的牵引力的能力，从而防止不可逆的纺锤体多极性和非整倍体。
