Chen Jing, Liu Jian
National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
Biophys J. 2015 Dec 1;109(11):2418-35. doi: 10.1016/j.bpj.2015.10.024.
To segregate chromosomes during cell division, microtubules that form the bipolar spindle attach to and pull on paired chromosome kinetochores. The spindle assembly checkpoint (SAC) is activated at unattached and misattached kinetochores to prevent further mitotic progression. The SAC is silenced after all the kinetochores establish proper and stable attachment to the spindle. Robust timing of SAC silencing after the last kinetochore-spindle attachment herein dictates the fidelity of chromosome segregation. Chromosome missegregation is rare in typical somatic cell mitosis, but frequent in cancer cell mitosis and in meiosis I of mammalian oocytes. In the latter cases, SAC is normally activated in response to disruptions of kinetochore-spindle attachments, suggesting that frequent chromosome missegregation ensues from faulty SAC silencing. In-depth understanding of how SAC silencing malfunctions in these cases is yet missing, but is believed to hold promise for treatment of cancer and prevention of human miscarriage and birth defects. We previously established a spatiotemporal model that, to the best of our knowledge, explained the robustness of SAC silencing in normal mitosis for the first time. In this article, we take advantage of the whole-cell perspective of the spatiotemporal model to identify possible causes of chromosome missegregation out of the distinct features of spindle assembly exhibited by cancer cells and mammalian oocytes. The model results explain why multipolar spindle could inhibit SAC silencing and spindle pole clustering could promote it-albeit accompanied by more kinetochore attachment errors. The model also eliminates geometric factors as the cause for nonrobust SAC silencing in oocyte meiosis, and instead, suggests atypical kinetochore-spindle attachment in meiosis as a potential culprit. Overall, the model shows that abnormal spindle-pole formation and its aberrant coordination with atypical kinetochore-spindle attachments could compromise the robustness of SAC silencing. Our model highlights systems-level coupling between kinetochore-spindle attachment and spindle-pole formation in SAC silencing.
在细胞分裂过程中，为了分离染色体，形成双极纺锤体的微管会附着并拉动配对的染色体动粒。纺锤体组装检查点（SAC）在未附着和错误附着的动粒处被激活，以防止有丝分裂进一步进行。在所有动粒与纺锤体建立适当且稳定的附着后，SAC会失活。最后一个动粒与纺锤体附着后，SAC失活的精确时间决定了染色体分离的保真度。染色体错分离在典型的体细胞有丝分裂中很少见，但在癌细胞有丝分裂和哺乳动物卵母细胞的减数分裂I中很常见。在后一种情况下，SAC通常会因动粒与纺锤体附着的破坏而被激活，这表明频繁的染色体错分离是由于SAC失活故障所致。目前尚缺乏对这些情况下SAC失活如何出现故障的深入理解，但人们认为这有望用于癌症治疗以及预防人类流产和出生缺陷。我们之前建立了一个时空模型，据我们所知，该模型首次解释了正常有丝分裂中SAC失活的稳健性。在本文中，我们利用时空模型的全细胞视角，从癌细胞和哺乳动物卵母细胞所展现的纺锤体组装的独特特征中，识别出染色体错分离的可能原因。模型结果解释了为什么多极纺锤体可以抑制SAC失活，而纺锤体极聚集可以促进SAC失活——尽管同时会伴随着更多的动粒附着错误。该模型还排除了几何因素是卵母细胞减数分裂中SAC失活不稳健的原因，相反，提示减数分裂中动粒与纺锤体的非典型附着是一个潜在原因。总体而言，该模型表明异常的纺锤体极形成及其与非典型动粒与纺锤体附着的异常协调可能会损害SAC失活的稳健性。我们的模型突出了在SAC失活过程中动粒与纺锤体附着和纺锤体极形成之间的系统水平耦合。
