The roles of Hop2 and Mndl in mouse meiotic homologous recombination

Hop2和Mndl在小鼠减数分裂同源重组中的作用

基本信息

批准号：
8466514
负责人：
Roberto Jose Pezza
金额：
$ 34.44万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8466514
关键词：
Address Aneuploidy Biochemical Bypass Catalysis Cell Nucleus Cells Chromosome Segregation Chromosomes Complex Congenital Abnormality DNA Double Strand Break DNA Repair Pathway Defect Development Developmental Biology Diagnosis Double Strand Break Repair Enzymes Eukaryota Exhibits Failure Generations Genetic Genetic Recombination Genome Goals Health Human Incidence Infertility Instruction Knockout Mice Mammals Mediating Meiosis Modeling Molecular Mus Oklahoma Pathway interactions Phenotype Plant Roots Play Positioning Attribute Property Proteins Regulation Role Sequence Homologs Single-Stranded DNA Sterility Structural Protein Structure System Testing Tissues Transgenic Mice Turner&apos s Syndrome Work base domain mapping ds-DNA homologous recombination in vivo insight prevent recombinase recombinational repair repaired segregation

项目摘要

PROJECT SUMMARY (See instructions): Homologous recombination is the only error-free system to repair DNA double-strand breaks. In meiosis, homologous recombination also provides temporal association between pairs of homologous chromosomes allowing their orderly segregation to opposite poles of dividing nuclei. This has a direct impact on faithful haploidization of a genome versus generation of aneuploidy. Indeed, failure of proper homologous chromosome segregation leads to infertility and severe aneuploid-based birth defects such as Down, Klinefelter, Edwards and Turner syndromes. At the center of the homologous recombination pathway is the step of strand invasion catalyzed by the ubiquitous Rad51 and the meiotic specific Dmcl recombinases. The proper functions of the recombinases require interaction with accessory proteins. Our central hypothesis is that two accessory proteins, Hop2 and Mndl, are essential for normal progression of homologous recombination and homologous chromosome segregation in mammalian meiosis. In part this may be explained by Hop2 and Mndl forming a heterodimer that stimulates strand invasion promoted by Dmcl and Rad51. In this proposal, we will use genetic and biochemical approaches to test this hypothesis and address fundamental questions about Mnd1 and Hop2 in higher eukaryotes: what are the structural determinants of the Hop2/Mnd1-Dmc1/Rad51 cooperation, and when and how do Mndl and Hop2 regulate the progression of homologous recombination in mammalian meiotic cells? Additionally, an important goal is to determine whether Hop2 by itself can function as a recombinase. If confirmed, our results will position Hop2 as the only ATP-independent meiotic recombinase and define a new pathway of DSB repair distinct from those promoted by Dmcl and Rad51. Through defining the roles of accessory proteins, the broader implication of our studies is to understand the contribution of homologous recombination in preventing homologous chromosome segregation defects leading to infertility and aneuploidy in humans.

项目摘要（参见说明）：同源重组是修复 DNA 双链断裂的唯一无差错系统。在减数分裂中，同源重组还提供同源染色体对之间的时间关联，允许它们有序地分离到分裂核的相对极。这对基因组的忠实单倍化与非整倍体的产生有直接影响。事实上，正确的同源染色体分离失败会导致不孕症和严重的非整倍体出生缺陷，例如唐氏综合症、克氏综合症、爱德华氏综合症和特纳综合症。同源重组途径的中心是由普遍存在的 Rad51 和减数分裂特异性 Dmcl 重组酶催化的链侵入步骤。重组酶的正常功能需要与辅助蛋白相互作用。我们的中心假设是，两种辅助蛋白 Hop2 和 Mndl 对于哺乳动物减数分裂中同源重组和同源染色体分离的正常进展至关重要。这在一定程度上可以通过Hop2和Mndl形成异二聚体来解释，该异二聚体刺激由Dmcl和Rad51促进的链入侵。在本提案中，我们将使用遗传和生化方法来检验这一假设，并解决高等真核生物中有关 Mnd1 和 Hop2 的基本问题：Hop2/Mnd1-Dmc1/Rad51 合作的结构决定因素是什么，以及 Mndl 和 Hop2 何时以及如何发挥作用。 Hop2 调节哺乳动物减数分裂细胞同源重组的进程？此外，一个重要的目标是确定 Hop2 本身是否可以充当重组酶。如果得到证实，我们的结果将把 Hop2 定位为唯一不依赖于 ATP 的减数分裂重组酶，并定义一条不同于 Dmcl 和 Rad51 所促进的 DSB 修复的新途径。通过定义辅助蛋白的作用，我们研究的更广泛意义是了解同源重组在防止同源染色体分离缺陷导致人类不育和非整倍性方面的贡献。