Molecular Control of Meiotic Chromosome Dynamics

减数分裂染色体动力学的分子控制

• 批准号: 10650807
• 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/10650807
• 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 Crossing Over; 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 Site; 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; transmission process; 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.

项目总结/摘要 有性繁殖的生物体依赖于减数分裂，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。错误在此 这一过程导致产生染色体数目异常或非整倍性的后代，这是 是人类流产和先天缺陷如唐氏综合症的主要原因。精确分离 染色体在减数分裂过程中需要配对，突触，并进行交叉重组与他们的 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，这些蛋白质对 在减数分裂过程中，这些蛋白质机器如何协同工作来驱动和协调， 染色体动力学我们的研究计划将结合这些基本过程， 使用纯化的组分进行生化分析，具有在高度浓缩的背景下检查减数分裂的能力。 易驾驭角秀丽隐杆线虫生殖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 但在调节交叉重组方面所起的作用却知之甚少。虽然遗传和细胞学 研究已经确定了各种生物体中的SC蛋白，各个组分如何相互作用， 形成SC的规则的、重复的排列在很大程度上是未知的。最近发现的两个新的SC 成分C.秀丽隐杆线虫SYP-5和SYP-6，使我们的小组能够独特地研究其结构， 我们将完善我们的纯化方案，以分离SYP蛋白复合物，并确定SC的功能。 化学计量和蛋白质-蛋白质之间的相互作用SC组分。这项工作将揭示 图SC，这将提供一个基础，了解其保守的结构在整个真核生物。 与此同时，我们将通过关键的细胞周期激酶和磷酸酶来描述信号级联，以建立关键的 控制同源配对、突触和减数分裂重组的调节机制。我们将确定 PLK-2调节SC动态特性及其对亲交换亲和力的机制 因素我们还将破译CDK多位点磷酸化密码如何激发开关样反应， 介导交叉指定。我们的研究将阐明减数分裂染色体的机制 行为的生物化学水平，并最终揭示了生物体如何忠实地传递遗传信息 从父母到后代