The spindle assembly checkpoint works like a rheostat rather than a toggle switch.
The spindle assembly checkpoint works like a rheostat rather than a toggle switch.
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DOI：
10.1038/ncb2855
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发表时间：
2013-11
影响因子：
21.3
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中科院分区：
文献类型：
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纺锤体组装检查点（SAC）是哺乳动物有丝分裂中确保姐妹染色单体平等分离的关键。SAC产生有丝分裂检查点复合物（MCC）以防止后期促进复合物/环体（APC/C）靶向关键的有丝分裂调节剂进行破坏，直到所有染色体都附着到有丝分裂器上。单个未附着的动粒可以延迟后期数小时，但它如何能够在整个细胞中阻断APC/C尚不清楚。SAC的当前概念表明，它表现出“全或无”响应，或者存在足以阻止APC/C的最小阈值。在这里，我们使用基因靶向来测量SAC活性，并发现它没有“全有或全无”的反应。相反，SAC的强度取决于被招募到着丝粒的Mad 2的量和形成的MCC的量。此外，我们发现不同的药物激活SAC的程度不同，这可能与它们在化疗中的疗效有关。
The Spindle Assembly Checkpoint (SAC) is essential in mammalian mitosis to ensure the equal segregation of sister chromatids. The SAC generates a Mitotic Checkpoint Complex (MCC) to prevent the Anaphase Promoting Complex/Cyclosome (APC/C) from targeting key mitotic regulators for destruction until all the chromosomes have attached to the mitotic apparatus. A single unattached kinetochore can delay anaphase for several hours, but how it is able to block the APC/C throughout the cell is not understood. Current concepts of the SAC posit that it exhibits either an ‘all or nothing’ response or there is a minimum threshold sufficient to block the APC/C. Here, we have used gene targeting to measure SAC activity and find that it does not have an ‘all or nothing’ response. Instead, the strength of the SAC depends on the amount of Mad2 recruited to kinetochores and on the amount of MCC formed. Furthermore, we show that different drugs activate the SAC to different extents, which may be relevant to their efficacy in chemotherapy.