Defining pathways of spindle checkpoint silencing: functional redundancy between Cdc20 ubiquitination and p31(comet).
Defining pathways of spindle checkpoint silencing: functional redundancy between Cdc20 ubiquitination and p31(comet).
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DOI：
10.1091/mbc.e11-05-0389
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发表时间：
2011-11
影响因子：
3.3
通讯作者：
Yu H
中科院分区：
文献类型：
--
作者：
Jia L;Li B;Warrington RT;Hao X;Wang S;Yu H
缺乏纺锤体检查点失活的一般分子框架。Mad 2抑制剂p31 comet具有独立于泛素-蛋白酶体途径的作用。这一关键发现允许描绘两个部分冗余的有丝分裂退出途径。纺锤体检查点在有丝分裂期间感知未附着或不正确附着的动粒，抑制后期促进复合物或细胞周期体（APC/C），并延迟后期开始以防止非整倍性。由BubR 1、Bub 3、Mad 2和Cdc 20组成的有丝分裂检查点复合物（MCC）是人类细胞中关键的APC/C抑制性检查点复合物。在中期-后期转换时，纺锤体检查点关闭，MCC解体以允许后期开始。检查点失活的分子机制知之甚少。一个主要的未解决的问题是Cdc 20 autoubiquitination在这个过程中的作用。虽然Cdc 20 autoubiquitination可以促进Mad 2解离Cdc 20，nonubiquitinatable Cdc 20突变体仍然解离Mad 2在检查点失活。在这里，我们表明，耗尽p31 comet延迟Mad 2解离Cdc 20突变体，不能进行autoubiquitination。因此，p31彗星和Cdc 20的泛素化是检查点失活的关键机制。它们冗余地促进Mad 2从Cdc 20解离。
A general molecular framework for spindle checkpoint inactivation is lacking. The Mad2 inhibitor, p31comet, has roles independent of the ubiquitin-proteasome pathway. This key finding allows the delineation of two partially redundant pathways for mitotic exit. The spindle checkpoint senses unattached or improperly attached kinetochores during mitosis, inhibits the anaphase-promoting complex or cyclosome (APC/C), and delays anaphase onset to prevent aneuploidy. The mitotic checkpoint complex (MCC) consisting of BubR1, Bub3, Mad2, and Cdc20 is a critical APC/C-inhibitory checkpoint complex in human cells. At the metaphase–anaphase transition, the spindle checkpoint turns off, and MCC disassembles to allow anaphase onset. The molecular mechanisms of checkpoint inactivation are poorly understood. A major unresolved issue is the role of Cdc20 autoubiquitination in this process. Although Cdc20 autoubiquitination can promote Mad2 dissociation from Cdc20, a nonubiquitinatable Cdc20 mutant still dissociates from Mad2 during checkpoint inactivation. Here, we show that depletion of p31comet delays Mad2 dissociation from Cdc20 mutants that cannot undergo autoubiquitination. Thus both p31comet and ubiquitination of Cdc20 are critical mechanisms of checkpoint inactivation. They act redundantly to promote Mad2 dissociation from Cdc20.