How Do Synaptonemal Complex Proteins Promote Crossover Recombination and Synapsis?

联会复合蛋白如何促进交叉重组和联会？

• 批准号: 10515002
• 负责人: Amy Joy MacQueen
• 金额: $ 49.29万
• 依托单位: WESLEYAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515002
• 关键词: Alleles; Aneuploidy; Architecture; Biochemical; Cell Cycle; Cell Nucleus; Cells; Chromosome Pairing; Chromosome Segregation; Chromosome Structures; Chromosomes; Clinical; Complex; Crystallization; Custom; Cytology; DNA; DNA Double Strand Break; DNA Repair; Data; Daughter; Dependence; Double Strand Break Repair; Elements; Environment; Event; Exhibits; Failure; Filament; Genetic; Genetic Crossing Over; Genetic Recombination; Germ Cells; Homologous Gene; Human; Label; Lead; Length; Ligase; Link; Mediating; Meiosis; Meiotic Recombination; Molecular; N-terminal; Organism; Pathway interactions; Phenotype; Phospho-Specific Antibodies; Phosphorylation; Ploidies; Pregnancy; Process; Proteins; Regulation; Research; Research Assistant; Research Proposals; Role; Saccharomyces cerevisiae; Saccharomycetales; Serine; Sexual Reproduction; Sister; Site; Structure; Students; Sumoylation Pathway; Synaptonemal Complex; Training; base; chromosome movement; cohesion; design; doctoral student; experimental study; member; mutant; protein complex; repaired; segregation; success; undergraduate student; yeast two hybrid system

Project Summary Our proposed research aims to decipher the molecular mechanisms that underlie homologous chromosome segregation during reproductive cell formation. Meiosis is the specialized cell division cycle that partitions the two homologous copies of every chromosome (homologs) to separate daughter nuclei, effectively reducing chromosome ploidy. Errors in chromosome segregation lead to aneuploid reproductive cells that carry too many or two few chromosomes. Key to the success of homolog segregation is the prior establishment of transient but stable associations between replicated chromosomes; for most organisms these links are formed by interhomolog crossover recombination events, in conjunction with intact sister cohesion. How crossover events are efficiently generated between every chromosome pair during meiosis remains poorly understood, but for most organisms it is clear that the process involves an exquisite coordination between large-scale chromosome movements and local DNA repair processes. A conserved multi-protein structure, the synaptonemal complex (SC), mediates an intimate alignment between homologous partner chromosome axes and forms the physical context in which DNA repair intermediates mature. SC has long been associated with successful crossover recombination, and although our recent research demonstrated that the SC structure per se is dispensable for crossing over in budding yeast, we also showed that the SC building block component, Zip1, has a genetically separable function in promoting crossovers. Our structure-function analysis revealed adjacent domains within Zip1’s N terminus that function independently to promote crossover recombination and SC assembly, potentially through separately interfacing with the pro-crossover E3 SUMO ligase, Zip3, and the SC central element protein complex Ecm11-Gmc2. Our recent data has i) revealed a potential phosphorylation-based switch in Zip1’s N terminus that controls its crossover activity, ii) identified several regions within the Zip3 protein required for its pro-recombination and/or pro-SC assembly activities, iii) narrowed the minimal interaction interface between Ecm11 and Gmc2, and iv) demonstrated proximity labeling interactions between pro-crossover proteins (and possibly SC central element proteins) that are stabilized by Zip1’s N terminus. Our proposed experiments, which are designed to support a uniquely rich training environment for several undergraduates, a new “5th year” Masters student, and one doctoral student, build upon our recent experimental data and aim to deepen our structural and functional understanding of the molecular mechanisms that coordinate recombination and SC assembly in S. cerevisiae.

项目概要 我们提出的研究旨在破译同源染色体的分子机制 生殖细胞形成过程中的分离是特殊的细胞分裂周期。 每条染色体的两个同源拷贝（同源物）用于分离子核，有效减少 染色体分离错误导致非整倍体生殖细胞也携带染色体倍性。 许多或两个少数染色体。 同源分离成功的关键是事先建立。 对于大多数生物体来说，复制的染色体之间存在短暂但稳定的关联； 通过同源间交叉重组事件，与完整的姐妹内聚力相结合。 减数分裂过程中每对染色体之间如何有效地产生交叉事件仍然存在 知之甚少，但对于大多数生物体来说，很明显该过程涉及精细的协调 大规模染色体运动和局部 DNA 修复过程之间的保守多蛋白。 结构，联会复合体（SC），介导同源伴侣之间的紧密排列 染色体轴并形成 DNA 修复中间体 SC 长期成熟的物理环境。 与成功的交叉重组有关，尽管我们最近的研究表明 SC 结构本身对于芽殖酵母中的交换来说是可有可无的，我们还表明 SC 结构 块组件 Zip1 在促进交叉方面具有遗传可分离的功能。 分析揭示了 Zip1 N 末端内的相邻结构域独立发挥作用以促进交叉 重组和 SC 组装，可能通过与专业交叉 E3 SUMO 单独连接 连接酶、Zip3 和 SC 中心元件蛋白复合物 Ecm11-Gmc2。 我们最近的数据 i) 揭示了 Zip1 的 N 末端存在一个潜在的基于磷酸化的开关，该开关控制着 其交叉活性，ii) 鉴定了 Zip3 蛋白内促重组所需的几个区域 和/或亲 SC 组装活动，iii) 缩小了 Ecm11 和 Gmc2 之间的最小相互作用界面， iv) 证明了亲交叉蛋白（可能还有 SC 中心蛋白）之间的邻近标记相互作用 我们提出的实验旨在稳定 Zip1 的 N 末端。 为多名本科生、新的“五年级”硕士生提供独特的丰富培训环境，以及 一名博士生，以我们最近的实验数据为基础，旨在深化我们的结构和功能 了解酿酒酵母中协调重组和 SC 组装的分子机制。

项目成果

Crossover recombination and synapsis are linked by adjacent regions within the N terminus of the Zip1 synaptonemal complex protein.

交叉重组和突触通过 Zip1 联会复合体蛋白 N 末端的相邻区域连接。

• DOI: 10.1371/journal.pgen.1008201
• 发表时间: 2019
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Voelkel-Meiman,Karen;Cheng,Shun-Yun;Parziale,Melanie;Morehouse,SavannahJ;Feil,Arden;Davies,OwenR;deMuyt,Arnaud;Borde,Valérie;MacQueen,AmyJ
• 通讯作者: MacQueen,AmyJ