Molecular Control of Meiotic Chromosome Dynamics

减数分裂染色体动力学的分子控制

• 批准号: 10406728
• 负责人: Yumi Kim
• 金额: $ 39.48万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406728
• 关键词: Affinity; Aneuploidy; Behavior; Biochemical; Caenorhabditis elegans; Cell Cycle; Cell Cycle Regulation; Cell division; Cells; Chromosome Pairing; Chromosome Segregation; Chromosomes; Code; Congenital Abnormality; Cytology; Down Syndrome; Eukaryota; Fertilization; Foundations; Genetic; Genetic Recombination; Genetic study; Genome; Germ Cells; Haploidy; Homologous Gene; Human; Individual; Lead; Light; Malignant Neoplasms; Maps; Mediating; Meiosis; Meiotic Recombination; Molecular; Organism; Parents; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Play; Positioning Attribute; Process; Production; Property; Prophase; Proteins; Protocols documentation; Public Health; Research; Role; Signal Transduction; Spontaneous abortion; Structure; Synapses; Synaptonemal Complex; Syp protein; Work; chromosome number abnormality; egg; genetic information; novel; offspring; programs; protein complex; protein protein interaction; response; scaffold; sperm cell; stoichiometry; zygote

Project Summary/Abstract Sexually reproducing organisms rely on meiosis, a specialized cell division that produces haploid gametes such as sperm and eggs, to restore the genetic content of the zygote through fertilization. Errors in this process lead to the production of offspring with an abnormal number of chromosomes or aneuploidy, and this is a major cause of human miscarriages and birth defects such as Down syndrome. Accurate segregation of chromosomes during meiosis requires that they pair, synapse, and undergo crossover recombination with their homologs. Although genetic studies over the decades have identified a list of proteins that are essential for meiotic processes, it remains largely unknown how these protein machines work together to drive and coordinate chromosome dynamics. Our research program will investigate these fundamental processes by combining biochemical analysis using purified components, with the ability to examine meiosis in the context of highly tractable C. elegans germline. One major focus of our work is the synaptonemal complex (SC), a proteinaceous scaffold that assembles between paired homologous chromosomes. The SC is a hallmark of meiotic prophase and yet plays a poorly understood role in regulating crossover recombination. Although genetic and cytological studies have identified SC proteins in various organism, how individual components interact with each other to form the regular, repetitive arrangement of the SC is largely unknown. The recent discovery of two novel SC components in C. elegans, SYP-5 and SYP-6, has uniquely positioned our group to investigate the structure and functions of the SC. We will refine our purification protocols to isolate SYP protein complexes and determine the stoichiometry and protein-protein interactions among the SC components. This work will reveal the molecular map of the SC, which will provide a foundation for understanding its conserved structure throughout eukaryotes. In parallel, we will delineate the signaling cascades by key cell cycle kinases and phosphatases to establish key regulatory mechanisms that govern homolog pairing, synapsis, and meiotic recombination. We will determine the mechanisms by which PLK-2 regulates the dynamic properties of the SC and its affinity to pro-crossover factors. We will also decipher how the CDK multisite phosphorylation code elicits a switch-like response and mediates crossover designation. Our studies will illuminate the mechanisms underlying meiotic chromosome behavior to a biochemical level and ultimately shed light into how organisms faithfully transmit genetic information from parent to progeny.

项目摘要/摘要 有性生殖有机体依赖于减数分裂，这是一种产生单倍体的特殊细胞分裂 配子，如精子和卵子，通过受精恢复受精卵的遗传内容。此中的错误 导致后代产生染色体数量异常或非整倍体的过程，这是 这是导致人类流产和唐氏综合症等出生缺陷的主要原因。准确的隔离 在减数分裂过程中，染色体需要配对、突触并与其进行交叉重组 同系物。尽管几十年来的遗传学研究已经确定了一系列蛋白质，这些蛋白质是 减数分裂过程中，很大程度上仍不清楚这些蛋白质机器是如何共同工作来驱动和协调的 染色体动力学。我们的研究计划将通过结合 使用纯化成分进行生化分析，能够在高度分离的情况下检查减数分裂 易驯化的线虫种系。我们工作的一个主要焦点是联会复合体(SC)，一种蛋白质 在成对的同源染色体之间组装的支架。SC是减数分裂前期的标志 然而，在调节交叉重组方面扮演的角色却鲜为人知。尽管遗传学和细胞学 研究已经确定了不同生物体中的SC蛋白，单个成分如何相互作用来 形成常规的、重复的SC安排在很大程度上是未知的。两种新型超临界流体的最新发现 线虫SYP-5和SYP-6中的成分，使我们的小组在研究结构和 执委会的职能。我们将完善我们的纯化方案，以分离SYP蛋白复合体并确定 SC组分之间的化学计量和蛋白质-蛋白质相互作用。这项工作将揭示分子 这将为理解其在真核生物中的保守结构提供基础。 同时，我们将通过关键的细胞周期激酶和磷酸酶来描绘信号级联，以建立关键的 管理同源配对、突触和减数分裂重组的调控机制。我们将决定 PLK-2调节SC的动态特性及其与亲交叉的亲和力的机制 各种因素。我们还将破译CDK多位点磷酸化密码如何引起开关样反应和 调解交叉指定。我们的研究将阐明减数分裂染色体的机制。 并最终揭示了生物是如何忠实地传递遗传信息的 从父母传给后代。