Regulation of meiotic chromosome segregation by post-translational modifications

虽然绝大多数细胞通过有丝分裂进行分裂，但生殖细胞经历一种特殊类型的分裂，称为减数分裂，这会导致配子的产生。减数分裂和有丝分裂都经历了一轮DNA复制，之后在这些分裂之间建立了明显的差异。当复制的DNA含量随后在子细胞之间分裂(与其亲本细胞相同)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复制后连续两轮的染色体分离实现的，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经历一次‘(遗传)信息交换’，这是遗传变异的一个重要来源。然后染色体被分开，这就是所谓的分离。在减数分裂II期，作为每条染色体的“一半”的染色单体被分离，最终从一个生殖细胞产生四个配子。一旦雄配子和雌配子受精，正常的DNA含量就会重新建立起来。虽然已经积累了大量与有丝分裂调控相关的知识，但对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确保染色体正确地分离成配子，我将使用线虫线虫，这是一种能够非常详细地研究减数分裂的多细胞有机体。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求给它们贴上不同的“旗帜”。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SUMO化。几十年来，人们对磷酸化进行了广泛的研究，并对其在有丝分裂中的作用进行了深入的研究。这不是苏莫化的情况，我和其他人的研究已经开始解决它在细胞分裂中的作用。在线虫中，减数分裂染色体分离是如何实现的还不清楚。虽然我最近已经证明，在分离之前，染色体在正确的时间处于正确的位置是重要的，但很明显，需要更广泛的观点来理解染色体分离是如何在卵母细胞中调节的，包括和化和磷酸化。这正是我要解决的问题。使用几种新的技术，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的研究，更好地了解苏莫化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，通过更好地了解线虫卵母细胞中染色体是如何分离的，我们将以一种也将改善人类生殖健康的方式丰富我们对减数分裂的总体理解。

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.