Understanding the triggers of mitotic exit using Drosophila

所有生物体都是由细胞组成的，细胞必须分裂才能确保繁殖、发育和生存。细胞分裂是一个复杂的过程，在进化过程中，受基因和蛋白质的分子机制控制，这些基因和蛋白质在物种之间很大程度上是保守的。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。我们利用遗传学、显微镜学、生物化学和分子生物学的强大结合来研究有丝分裂和减数分裂的调节机制。在细胞分裂过程中，染色体的分离受到很好的控制，以避免可能危及生存能力的错误。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共同作用，以触发染色体在中期-后期转变时的分离。这个事件开始完成核分裂，也称为有丝分裂结束。*** *在有丝分裂和减数分裂中，当后期促进复合体（APC）被激活时，染色体分离开始。APC是一种大型酶复合物，它修饰其他蛋白质，诱导其降解，并引发一系列事件，导致将染色体连接在一起的称为内聚蛋白的分子“胶水”的去除。有丝分裂器可以在后期将染色体分开。一种称为纺锤体组装检查点（SAC）的复杂分子机制确保在APC被激活之前所有染色体都正确定位。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的激活需要CycB3-Cdk1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它们的活性来起作用，但精确的分子机制尚不清楚。在未来的5年里，这个研究项目将阐明这一机制。我们还发现了一种名为PP2A-Tws的磷酸酶，它与CycB3-Cdk1协同激活APC。我们的目标是了解潜在的机制。最后，特别强调将放在表征这些和其他调节细胞分裂的机制的时空方面。酶如何利用细胞内定位的变化来控制其分裂程序还未得到充分的研究。*** *这项研究的动机是希望对真核生物中控制细胞分裂的基本机制有更全面的了解。这也是为培养新一代科学家做出贡献的一种手段，这些科学家将在学术界、工业界或政府中为我们社会的进步发挥积极作用。

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.