Regulation of meiotic chromosome segregation by post-translational modifications

虽然绝大多数细胞通过有丝分裂分裂，但生殖细胞会经历一种称为减数分裂的特殊分裂，从而产生配子。减数分裂和有丝分裂都经历一轮DNA复制，之后这些分裂之间建立了明显的区别。当复制的DNA含量在两个子细胞（与它们的亲本细胞相同）之间分裂时，减数分裂是减少的，因为配子中的DNA含量减少到亲本细胞的一半。这是通过DNA复制后连续两轮染色体分离实现的，称为减数分裂I和减数分裂II。在减数分裂1中，同源染色体相互识别并进行“（遗传）信息交换”，这是遗传变异的重要来源。然后染色体被拉开，这就是所谓的分离。在减数分裂II中，染色单体（每条染色体的“一半”）被分离，最终从一个生殖细胞中产生四个配子。一旦雄性和雌性配子受精，正常的DNA含量就会重新建立起来。虽然有丝分裂的调控已经积累了大量的知识，但对于生殖细胞用来保证忠实的减数分裂染色体分离的机制知之甚少。为了更好地理解生殖细胞使用什么机制来保证正确的染色体分离成配子，我将使用线虫C. elegans，一种可以非常详细地研究减数分裂的多细胞生物。细胞调节蛋白质功能的一种非常快速有效的方法是根据细胞的特定需要在蛋白质上附加不同的“标记”。这些标记被称为翻译后蛋白质修饰，我对其中的两个特别感兴趣：磷酸化和聚合化。磷酸化已经被广泛研究了几十年，它对有丝分裂的贡献得到了彻底的解决。这不是sumoylation的情况，我和其他人的研究已经开始解决它在细胞分裂中的作用。在秀丽隐杆线虫中，减数分裂染色体分离是如何实现的尚不清楚。虽然我最近表明，在分离之前，聚合化对于染色体“在正确的时间处于正确的位置”很重要，但很明显，需要一个更广泛的视角，包括聚合化和磷酸化，才能理解卵母细胞中染色体分离是如何调节的。这正是我要解决的问题。使用几种新颖的技术，其中许多是我自己开发的，我处于一个独特的位置来解决这个问题，并提供非常有价值的见解。我将结合体外和体内研究，更好地了解summoylation和磷酸化如何调节减数分裂过程中的蛋白质功能，从而更好地了解减数分裂染色体动力学是如何调节的。我的目标是，通过更好地了解秀丽隐杆线虫卵母细胞中染色体是如何分离的，我们将以一种改善人类生殖健康的方式丰富我们对减数分裂的理解。

While the vast majority of cells divide through mitosis, germ cells undergo a specialised type of division called meiosis, which leads to the generation of gametes. Both meiosis and mitosis undergo a round of DNA replication, after which a clear difference is established between these divisions. While the duplicated DNA content is then divided between to daughter cells (identical to their parent cell), the meiotic division is reductional, as the DNA content in the gametes is reduced to half that of the parent cell. This is achieved by two successive rounds of chromosome segregation after DNA replication, called meiosis I and meiosis II. In meiosis one, homologous chromosomes recognise each other and undergo an 'exchange of (genetic) information', which is a great source of genetic variability. The chromosomes are then pulled apart in what is called segregation. During meiosis II, the chromatids, which are the 'halves' of each chromosome are segregated, ultimately generating four gametes from one germ cell. Once the male and female gametes undergo fertilisation, the normal DNA content is re-established. While a great deal of knowledge has accumulated related to the regulation of mitosis, far less is is known about the mechanisms germ cells utilise to guarantee faithful meiotic chromosome segregation. To better understand what mechanisms germ cells use to guarantee correct chromosome segregation into gametes, I will use the nematode C. elegans, a multicellular organism ameanable to study meiosis in great detail. A very fast and efficient way for cells to regulate protein function is to attach different 'flags' to them depending on the specific needs of the cell. These flags are called post-translational protein modifications and I am specifically interested in two of them: phosphorylation and sumoylation. Phosphorylation has been extensively studied for decades and its contribution to the mitotic division thoroughly addressed. This is not the case of sumoylation, and studies by myself and others have begun to address its role during cell division. In C. elegans, how meiotic chromosome segregation is achieved is not understood. While I have recently shown that sumoylation is important for chromosomes to 'be in the right place at the right time' prior to segregation, it has become clear that a wider view that includes both sumoylation and phosphorylation is required to understand how chromosome segregation is regulated in oocytes. This is exactly what I will address. Using several novel techniques, many of which I have developed myself, I am in a unique position to address this issue and contribute very valuable insights. I will combine in vitro and in vivo studies to better understand how sumoylation and phosphorylation regulate protein function during meiosis and thus have a better understanding of how meiotic chromosome dynamics is regulated.It is my goal that, by providing a better understanding of how chromosomes segregate in C. elegans oocytes, we will enrich our understanding of meiosis in general in a way that reproductive health will be improved for humans as well.