Sex-specific regulation of meiosis

减数分裂的性别特异性调节

• 批准号: 9900011
• 负责人: JOANNE ENGEBRECHT
• 金额: $ 30.59万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-05 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9900011
• 关键词: ATR gene; Address; Aneuploidy; Animal Model; BARD1 gene; BRCA1 gene; Behavior; Biochemical; Biological; Caenorhabditis elegans; Cell Cycle; Cell division; Cells; Chromosome Segregation; Chromosomes; Complex; Congenital Abnormality; Coupled; Coupling; Cytology; DNA; DNA Damage; DNA Repair; Data; Development; Disease; Down Syndrome; Embryo; Ensure; Equilibrium; Event; Excision; Female; Filament; Frequencies; Gametogenesis; Genetic; Genetic Epistasis; Genetic Recombination; Genome; Germ Cells; Haploidy; Health; Homologous Gene; Human; Infertility; Kinetochores; Lead; Malignant Neoplasms; Mammals; Mediating; Meiosis; Meiotic Recombination; Microtubules; Mitogen-Activated Protein Kinases; Modeling; Molecular; Monitor; Morphology; Mutation; Nonhomologous DNA End Joining; Oocytes; Oogenesis; Pathology; Pathway interactions; Phosphorylation; Play; Positioning Attribute; Process; Production; Regulation; Reproduction; Role; Sex Differences; Signal Transduction; Site; Somatic Cell; Spermatocytes; Spermatogenesis; Spontaneous abortion; System; Testing; Tumor Suppressor Proteins; Work; ataxia telangiectasia mutated protein; developmental disease; egg; experimental study; genome editing; genome integrity; homologous recombination; in vivo; insight; male; next generation; novel; programs; repaired; reproductive success; response; sex; sexual dimorphism; sperm cell; tool; transmission process; ubiquitin-protein ligase

Meiosis is a specialized form of cell division that leads to the production of two distinct gamete types, sperm and egg, for sexual reproduction. In addition to a haploid set of chromosomes, sperm and egg must provide the embryo with unique but complementary products to support development. To accomplish this, the meiotic program is sexual dimorphic; however, the mechanisms underlying differences in male and female meiosis have remained elusive. We have identified sex-specific roles for the tumor suppressor E3 ubiquitin ligase BRCA1/BARD1 complex in meiotic recombination, and in checkpoint signaling, and thus are uniquely positioned to determine the underlying molecular mechanisms regulating meiosis in the sexes. Our overall hypothesis is that sex-specific differences in recombination and checkpoint signaling serve to balance the accurate transmission of the genome with overall reproductive success. To test this hypothesis, we propose to elucidate conserved mechanisms underlying chromosome behavior during male and female meiosis using the simple metazoan animal model Caenorhabditis elegans, which overcomes many technical challenges inherent in mammalian systems. In Aim 1 we will determine mechanistically how BRCA1/BARD1 mediates double-strand break processing in male versus female germ cells, using targeted genetic, cell biological and biochemical approaches. We will also determine the significance of E3 ubiquitin ligase activity to BRCA1/BARD1 function in meiosis. In Aim 2 we will elucidate mechanisms underlying how BRCA1/BARD1 is regulated to perform the sex-specific functions defined in Aim 1. In Aim 3 we will uncover the role of BRCA1/BARD1 in checkpoint signaling under conditions where there are errors in recombination and chromosome alignment to determine mechanisms underlying the fidelity of male meiosis. Together, an understanding of these processes in the genetically tractable C. elegans system will provide novel and important insights into how the meiotic program is regulated in a sex-specific manner. These studies have direct relevance to understanding the increased frequency of errors associated with human meiosis resulting in developmental disorders such as Down’s Syndrome. Importantly, these studies will also elucidate general mechanisms of, and the involvement of BRCA1/BARD1 in, DNA repair, chromosome segregation and checkpoint signaling, events that play critical roles in maintaining genome integrity in all cells.

减数分裂是一种特殊的细胞分裂形式，导致产生两种不同的配子类型，即精子 卵子，用于有性繁殖。除了一组单倍体的染色体外，精子和卵子必须提供 胚胎具有独特但互补的产品来支持发育。要做到这一点，减数分裂 程序是性别二态的；然而，男性和女性减数分裂的潜在差异的机制 仍然难以捉摸。我们已经确定了肿瘤抑制基因E3泛素连接酶的性别特异性作用 BRCA1/BARD1复合体在减数分裂重组和检查点信号传递中，因此是独一无二的 定位于确定调节两性减数分裂的潜在分子机制。我们的整体 假设重组和检查点信号的性别差异有助于平衡 基因组的准确传递和总体繁殖成功。为了检验这一假设，我们 建议阐明男性和女性染色体行为的保守机制 利用简单的后生动物模型秀丽线虫进行减数分裂，克服了许多技术上的困难 哺乳动物系统固有的挑战。在目标1中，我们将机械地确定BRCA1/BARD1如何 使用靶向遗传细胞，在男性生殖细胞与女性生殖细胞之间介导双链断裂处理 生物和生化方法。我们还将确定E3泛素连接酶活性对 BRCA1/BARD1在减数分裂中的作用。在目标2中，我们将阐明BRCA1/BARD1是如何 执行目标1中定义的特定性别的功能。在目标3中，我们将揭示 BRCA1/BARD1在重组和出现错误的情况下的检查点信令 染色体配对，以确定男性减数分裂保真度的潜在机制。团结在一起，一个 了解易遗传的线虫系统中的这些过程将提供新的和 对减数分裂计划如何以性别特有的方式进行调控的重要见解。这些研究已经 与理解与人类减数分裂相关的错误频率增加直接相关 发育障碍，如唐氏综合症。重要的是，这些研究还将阐明一般情况 BRCA1/BARD1在DNA修复、染色体分离和细胞周期调控中的作用机制 检查点信号，在维持所有细胞基因组完整性方面发挥关键作用的事件。