How does the spindle checkpoint convert Cdc20 into an APC/C substrate?

主轴检查点如何将 Cdc20 转化为 APC/C 底物？

• 批准号: BB/G001537/1
• 负责人: Jonathon Pines
• 金额: $ 32.53万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2008
• 资助国家: 英国
• 起止时间: 2008 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FG001537%2F1
• 关键词: How; does; spindle; checkpoint; convert

It is crucial that cell division should generate two identical daughter cells. The daughter cells recieve an exact copy of the genetic material from the original cell. The distribution of the genetic material in the form of chromosomes is monitored carefully by the cell during cell division. The system monitoring this process is referred to as the Spindle Assembly Checkpoint. If the Spindle Assembly Checkpoint is not working properly the daughter cells will not get an exact copy of the genetic material. This results in an unequal number of chromosomes being passed to the two daughters and this is called called aneuploidy. Recent research indicates that aneuploidy can initiate tumor formation and indeed many tumor cell lines appear to have a weak Spindle Assembly Checkpoint. We are focusing our efforts on trying to understand how the Spindle Assembly Checkpoint functions in normal cells, and to gain insight into why it might become defective in tumors. We know the Spindle Assembly Checkpoint inhibits the protein Cdc20. Cdc20 is an activator of a large complex called the Anaphase Promoting Complex/Cyclosome (APC/C) that is responsible for degrading specific proteins in mitosis. Two components of the Spindle Assembly Checkpoint namely Mad2 and BubR1 bind directly to Cdc20 and are responsible for this inhibition. We have recently found that not only does the Spindle Assembly Checkpoint inhibit Cdc20 but it also targets Cdc20 for degradation via APC/C. This means that when the Spindle Assembly Checkpoint is active Cdc20 switches from an activator of the APC/C to a substrate. We have also shown that this degradation of Cdc20 is important for maintaining an active checkpoint. We now want to understand how the Spindle Assembly Checkpoint turns Cdc20 into a substrate of the APC/C and we are particular focusing on the role of BubR1 in this aspect since this appear to be the key component responsible for this. For BubR1 to target Cdc20 for degradation it needs to be able to bind to Cdc20. We have found that Mad2 is absolutely essential for the binding of BubR1 to Cdc20 and we will investigate why this is so.

细胞分裂产生两个相同的子细胞是至关重要的。子细胞从原始细胞获得遗传物质的精确拷贝。染色体形式的遗传物质的分布在细胞分裂期间由细胞仔细监测。监控此过程的系统称为主轴装配检查点。如果纺锤体组装检查点不能正常工作，子细胞将无法获得遗传物质的精确拷贝。这导致了不相等数量的染色体传递给两个女儿，这就是所谓的非整倍性。最近的研究表明，非整倍体可以启动肿瘤形成，并且实际上许多肿瘤细胞系似乎具有弱的纺锤体组装检查点。我们正集中精力试图了解纺锤体组装检查点在正常细胞中的功能，并深入了解为什么它可能在肿瘤中有缺陷。我们知道纺锤体组装检查点抑制蛋白Cdc 20。Cdc 20是一种称为后期促进复合物/环体（APC/C）的大型复合物的激活剂，该复合物负责降解有丝分裂中的特定蛋白质。纺锤体组装检查点的两个组分，即Mad 2和BubR 1直接结合Cdc 20，并负责这种抑制。我们最近发现，主轴组装检查点不仅抑制Cdc 20，而且还通过APC/C靶向Cdc 20进行降解。这意味着当主轴组件检查点激活时，Cdc 20从APC/C的激活器切换到衬底。我们还表明，Cdc 20的这种降解对于维持活跃的检查点很重要。我们现在想了解主轴组装检查点如何将Cdc 20转变为APC/C的基底，我们特别关注BubR 1在这方面的作用，因为这似乎是负责此的关键组件。为了使BubR 1靶向Cdc 20进行降解，它需要能够与Cdc 20结合。我们已经发现Mad 2对于BubR 1与Cdc 20的结合是绝对必要的，我们将研究为什么会这样。

项目成果

APC15 drives the turnover of MCC-CDC20 to make the spindle assembly checkpoint responsive to kinetochore attachment.

• DOI: 10.1038/ncb2347
• 发表时间: 2011-09-18
• 期刊: Nature cell biology
• 影响因子: 21.3

The spindle assembly checkpoint works like a rheostat rather than a toggle switch.

• DOI: 10.1038/ncb2855
• 发表时间: 2013-11
• 期刊: Nature cell biology
• 影响因子: 21.3