The role of Ipl1-dependent phosphorylation of Mad3p in the spindle checkpoint mechanism that restrains anaphase when sister kinetochores lack tension

当姐妹动粒缺乏张力时，Ipl1依赖性Mad3p磷酸化在抑制后期的纺锤体检查点机制中的作用

• 批准号: BB/F009453/1
• 负责人: Michael Stark
• 金额: $ 45.44万
• 依托单位: University of Dundee
• 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%2FF009453%2F1
• 关键词: role; Ipl1; dependent; phosphorylation; Mad3p

When cells divide, each chromosome is precisely copied and then one copy is distributed to each of the two daughter cells. The accuracy of this distribution process, termed chromosome segregation, is clearly vital since mistakes will result in chromosome loss in one daughter cell and gain chromosome gain in the other. Cells therefore have evolved mechanisms to ensure the accuracy of this process. The chromosomes are segregated to the two daughter cells by becoming attached to molecular cables, termed microtubules, that eventually pull them in opposite directions, but if this attachment is incorrect or fails to happen then segregation during division will fail. Cells therefore have mechanisms both to correct the attachment of chromosomes to microtubules when there is a problem, and to delay the cell from trying to divide until all chromosomes are correctly attached. The mechanism that delays cell division in response to incorrectly attached chromosomes it is present in all higher organisms and much of the work leading to our current understanding of the checkpoint mechanism has been carried out in yeast, a model organism that is used for investigating fundamental questions concerning how cells function. We have been using yeast to investigate the function of a regulatory protein involved in correcting the attachment of chromosomes to microtubules, and discovered that in addition to this function it also provides the signal that delays division while the correction process occurs. However, whereas until now the main factor demonstrated to delay division is the presence of chromosomes that are not attached to microtubules, the mechanism we have discovered appears to respond to chromosomes that are attached to microtubules but not subject to pulling forces exerted by them. This is the situation that would prevail if both copies of a chromosome became incorrectly attached to microtubules such that they would subsequently pull them into the same daughter cell. The objectives of our proposed work are therefore to understand how this new mechanism functions, since it may be the major pathway by which cells allow time to correct an important category of incorrectly attached chromosomes. By investigating how this mechanism operates at the molecular level, we will improve our understanding of a fundamental process that ensures the maintenance of genome integrity during cell division and that is relevant to human conditions such as cancer and Down's syndrome, where chromosome loss or gain events play an important role.

当细胞分裂时，每条染色体都被精确复制，然后将一个副本分配给两个子细胞。这种被称为染色体分离的分布过程的准确性显然是至关重要的，因为错误会导致一个子细胞的染色体丢失，而另一个子细胞获得染色体的增加。因此，细胞已经进化出机制来确保这一过程的准确性。染色体通过附着在被称为微管的分子缆线上被分离到两个子细胞上，分子缆线最终将它们拉向相反的方向，但如果这种附着不正确或未能发生，那么分裂过程中的分离将失败。因此，细胞既有机制在出现问题时纠正染色体与微管的连接，也有机制推迟细胞尝试分裂，直到所有染色体正确连接。对错误附着的染色体做出反应而延迟细胞分裂的机制存在于所有高等生物体中，导致我们目前对检查点机制的理解的许多工作都是在酵母中进行的，酵母是一种用于研究细胞如何功能的基本问题的模式生物。我们一直在使用酵母来研究一种参与纠正染色体与微管附着的调节蛋白的功能，并发现除了这一功能外，它还提供了在纠正过程发生时推迟分裂的信号。然而，尽管到目前为止被证明延迟分裂的主要因素是没有附着在微管上的染色体的存在，但我们已经发现的机制似乎对附着在微管上的染色体有反应，但不受它们施加的拉力的影响。如果染色体的两个副本都错误地附着在微管上，以至于它们随后会将它们拉入同一子细胞，这种情况就会发生。因此，我们提出的工作的目标是了解这一新机制是如何发挥作用的，因为它可能是细胞允许时间纠正一类重要的错误连接的染色体的主要途径。通过研究这一机制是如何在分子水平上运作的，我们将提高我们对一个基本过程的理解，该过程确保了细胞分裂期间保持基因组的完整性，并与癌症和唐氏综合症等人类疾病相关，在这些疾病中，染色体丢失或获得事件起着重要作用。

项目成果

Temperature-sensitive ipl1-2/Aurora B mutation is suppressed by mutations in TOR complex 1 via the Glc7/PP1 phosphatase.

TOR 复合物 1 的突变通过 Glc7/PP1 磷酸酶抑制温度敏感的 ipl1-2/Aurora B 突变。

• DOI: 10.1073/pnas.1014406108
• 发表时间: 2011
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Tatchell K