Sex-specific regulation of meiosis

减数分裂是细胞分裂的一种特殊形式，导致产生两种不同的配子类型，精子 和卵子进行有性繁殖除了一套单倍体染色体，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。为了实现这一点，减数分裂 程序是性的二态性;然而，机制的差异，男性和女性减数分裂 仍然难以捉摸我们已经确定了肿瘤抑制因子E3泛素连接酶的性别特异性作用 BRCA 1/BARD 1复合物在减数分裂重组和检查点信号传导中的作用，因此是独特的 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 假设是重组和检查点信号传导中的性别特异性差异有助于平衡 基因组的准确传递和整体繁殖成功。为了验证这个假设，我们 建议阐明男性和女性染色体行为的保守机制， 减数分裂使用简单的后生动物模型秀丽隐杆线虫，其克服了许多技术 哺乳动物系统固有的挑战。在目标1中，我们将从机制上确定BRCA 1/BARD 1 使用靶向遗传细胞介导雄性与雌性生殖细胞中的双链断裂处理 生物学和生物化学方法。我们还将确定E3泛素连接酶活性的意义， BRCA 1/BARD 1在减数分裂中的功能。在目标2中，我们将阐明BRCA 1/BARD 1是如何在细胞内表达的机制。 调节以执行目标1中定义的性别特异性功能。在目标3中，我们将揭示 BRCA 1/BARD 1在检查点信号传导中的作用， 染色体比对以确定雄性减数分裂保真度的潜在机制。合计的 在遗传上易处理的C. elegans系统将提供新颖的， 对减数分裂程序如何以性别特异性方式进行调节的重要见解。这些研究 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的 BRCA 1/BARD 1参与DNA修复、染色体分离和 检查点信号传导，在维持所有细胞中基因组完整性方面发挥关键作用的事件。

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.