Understanding the triggers of mitotic exit using Drosophila

所有生物体都是由细胞组成的，这些细胞必须分裂以确保繁殖，发育和生存。细胞分裂是一个复杂的过程，由涉及基因和蛋白质的分子机制控制，这些基因和蛋白质在进化过程中在物种之间基本上是保守的。这项研究计划旨在破译这些机制。为此，我们使用果蝇作为模型系统。几十年来，这种生物一直被用来研究生物学中的几个重要过程。我们使用遗传学，显微镜，生物化学和分子生物学的强大组合来研究调节有丝分裂和减数分裂的机制。细胞分裂期间染色体的分离被精细地控制，以避免会损害生存力的错误。在接下来的五年里，我们将专注于确定关键酶如何在时间和空间上协同工作，以触发染色体在中期-后期过渡期的分离。这一事件启动了核分裂的完成，也称为有丝分裂退出。 * 在有丝分裂和减数分裂中，当后期促进复合物（APC）被激活时，染色体分离开始。APC是一种大的酶复合物，它修饰其他蛋白质以诱导它们的降解，并启动一系列事件，导致去除将染色体保持在一起的称为粘着蛋白的分子“胶水”。有丝分裂器可以在分裂后期将染色体拉开。一种称为纺锤体组装检查点（SAC）的复杂分子机制确保所有染色体在APC被激活之前正确定位。然而，APC如何被激活仍然知之甚少。最近发现，在减数分裂中，APC激活需要CycB 3-Cdk 1酶。由于它是一种激酶，这种酶必须通过向其他蛋白质添加磷酸基团来改变其活性，但确切的分子机制尚不清楚。在未来5年内，该研究计划将阐明这一机制。我们还发现了一种名为PP 2A-Tws的磷酸酶，它与CycB 3-Cdk 1协同激活APC。我们的目标是了解潜在的机制。最后，将特别强调这些和其他机制调节细胞分裂的时空方面的特点。酶如何利用细胞内定位的变化来控制其分裂程序还没有得到充分的研究。 * 这项研究的动机是希望更全面地了解控制真核生物细胞分裂的基本机制。这也是一种手段，有助于培养新一代的科学家，他们将有能力在我们的社会进步中发挥积极作用，无论是在学术界，工业界还是政府。

All living organisms are made of cells that must divide to ensure reproduction, development and survival. Cell division is a complex process that is controlled by molecular mechanisms involving genes and proteins that have been largely conserved between species during evolution. This research program aims to decipher these mechanisms. To this end, we use the fruit fly Drosophila as a model system. This organism has been used for decades to investigate several important processes in biology. We use a powerful combination of genetics, microscopy, biochemistry and molecular biology to study the mechanisms regulating mitosis and meiosis. The segregation of chromosomes during cell division is finely controlled in order to avoid errors that would compromise viability. In the next five years, we will focus on determining how key enzymes work together in time and space to trigger the segregation of chromosomes at the metaphase-anaphase transition. This event initiates the completion of nuclear division, also known as mitotic exit.*** *In both mitosis and meiosis, chromosome segregation begins when the Anaphase Promoting Complex (APC) is activated. The APC is a large enzymatic complex that modifies other proteins to induce their degradation and initiate a cascade of events that leads to the removal of the molecular "glue" called cohesins that holds chromosomes together. The mitotic apparatus can then pull chromosomes apart in anaphase. A complex molecular mechanism known as the Spindle Assembly Checkpoint (SAC) ensures that all chromosomes are correctly positioned before the APC can be activated. However, how the APC is activated remains poorly understood. It was recently discovered that, in meiosis, APC activation requires the CycB3-Cdk1 enzyme. As it is a kinase, this enzyme must function by adding phosphate groups to other proteins to modify their activities, but the precise molecular mechanism is unknown. In the next 5 years, this research program will elucidate this mechanism. We have also found a phosphatase enzyme named PP2A-Tws that collaborates with CycB3-Cdk1 in activating the APC. We aim to understand the underlying mechanism. Finally, a special emphasis will be placed on characterizing the spatio-temporal aspects of these and other mechanisms regulating cell division. How enzymes use changes in localization inside the cell to control its division program has been underexplored.*** *This research is motivated by the desire to gain a more complete understanding of the fundamental mechanisms that control cell division in eukaryotes. It is also a means to contribute to the training of a new generation of scientists that will be equipped to play an active role in the advancement of our society, whether in academia, industry or governments.