Regulation of meiotic chromosome segregation by post-translational modifications

通过翻译后修饰调节减数分裂染色体分离

• 批准号: MR/R008574/1
• 负责人: Federico Pelisch
• 金额: $ 161.09万
• 依托单位: University of Dundee
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR008574%2F1
• 关键词: Regulation; meiotic; chromosome; segregation; post

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.

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称为减数分裂的特殊类型的分裂，这导致配子的产生。减数分裂和有丝分裂都经历一轮DNA复制，之后在这些分裂之间建立了明显的差异。虽然复制的DNA含量然后在子细胞（与其亲本细胞相同）之间分配，但减数分裂是还原性的，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来实现的，称为减数分裂I和减数分裂II。在减数分裂中，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。在第二次减数分裂期间，染色单体，也就是每条染色体的“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。虽然积累了大量的知识有关的有丝分裂的调控，远不知道的机制，生殖细胞利用，以确保忠实的减数分裂染色体分离。为了更好地理解生殖细胞使用什么机制来保证染色体正确地分离到配子中，我将使用线虫C。秀丽线虫是一种多细胞生物，可以详细研究减数分裂。细胞调节蛋白质功能的一种非常快速和有效的方法是根据细胞的具体需要给它们贴上不同的“标志”。这些标记被称为翻译后蛋白质修饰，我对其中两个特别感兴趣：磷酸化和sumoylation。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。In C.在线虫中，减数分裂染色体分离是如何实现的尚不清楚。虽然我最近已经表明，sumoylation是重要的染色体“在正确的时间在正确的地方”分离之前，它已经变得很清楚，一个更广泛的观点，包括sumoylation和磷酸化是需要了解如何在卵母细胞染色体分离调节。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。我将联合收割机的体外和体内研究相结合，以更好地了解SUMO化和磷酸化在减数分裂过程中如何调节蛋白质的功能，从而更好地了解减数分裂染色体动力学是如何调节的。线虫卵母细胞，我们将丰富我们对减数分裂的理解，以改善人类的生殖健康。

项目成果

BUB-1 targets PP2A:B56 to regulate chromosome congression during meiosis I in C. elegans oocytes

BUB-1 靶向 PP2A:B56 调节线虫卵母细胞减数分裂 I 期间的染色体会聚

• DOI: 10.1101/2020.06.12.148254
• 发表时间: 2020
• 作者: Borja L

BUB-1 targets PP2A:B56 to regulate chromosome congression during meiosis I in C. elegans oocytes.

• DOI: 10.7554/elife.65307
• 发表时间: 2020-12-23
• 期刊: eLife
• 影响因子: 7.7
• 作者: Bel Borja L;Soubigou F;Taylor SJP;Fraguas Bringas C;Budrewicz J;Lara-Gonzalez P;Sorensen Turpin CG;Bembenek JN;Cheerambathur DK;Pelisch F
• 通讯作者: Pelisch F

Sumoylation regulates central spindle protein dynamics during chromosome segregation in oocytes

Sumoylation 调节卵母细胞染色体分离过程中的中心纺锤体蛋白动态

• DOI: 10.1101/584763
• 发表时间: 2019
• 作者: Pelisch F

BUB-1 and CENP-C recruit PLK-1 to control chromosome alignment and segregation during meiosis I in C. elegans oocytes.

• DOI: 10.7554/elife.84057
• 发表时间: 2023-04-17
• 期刊: eLife
• 影响因子: 7.7
• 作者: Taylor SJP;Bel Borja L;Soubigou F;Houston J;Cheerambathur DK;Pelisch F
• 通讯作者: Pelisch F

BUB-1 and CENP-C recruit PLK-1 to Control Chromosome Alignment and Segregation During Meiosis I in C. elegans Oocytes

BUB-1 和 CENP-C 招募 PLK-1 来控制线虫卵母细胞减数分裂 I 期间的染色体排列和分离

• DOI: 10.1101/2022.10.07.511262
• 发表时间: 2022
• 作者: Taylor S