Regulation of the meiotic cell cycle

描述(申请人提供)：非整倍体是人类流产和智力低下的主要原因。因此，确定减数分裂染色体错误分离的原因对于理解唐氏综合症和不孕症的原理至关重要。我们研究的长期目标是确定在减数分裂过程中防止染色体错误分离从而防止非整倍体的机制。减数分裂是一种特殊的细胞分裂，在此过程中，单个DNA复制阶段之后是两个连续的染色体分离阶段(减数分裂I和减数分裂II)。减数分裂特异因子作用于与六个Clb细胞周期蛋白(Clb-CDKs)相关的细胞周期蛋白依赖性蛋白依赖性激酶(CDK)的CDc28，从而导致独特的减数分裂程序。这笔赠款有两个目标。(1)研究Clb-CDKs对减数分裂的调控作用。(2)我们想要描述CDK及其调控因子在减数分裂过程中发生的变化，并确定导致这些变化的减数分裂特异性调控因子。在特定的目标1中，我们将确定在减数分裂II过程中阻止Clb1-CDK活性的机制，并检查这一调控的重要性。在特定目标2中，我们将研究细胞周期蛋白CLB3的翻译是如何被控制的。抑制CLB3的翻译是减数分裂I染色体分离所必需的。因此，了解CLB3翻译是如何控制的，以及CLB3是如何抑制减数分裂I的，对于理解减数分裂I染色体分离模式的建立是至关重要的。在特定的目标3中，我们将确定CLB3如何抑制减数分裂I染色体分离。由于基本的细胞分裂机制从酵母到人类是高度保守的，并且考虑到本提案中描述的大多数因素也被证明控制哺乳动物的减数分裂，所以控制减数分裂的过程很可能也将在不同物种之间保守。因此，与许多其他细胞周期研究一样，在酵母中发现并表征的调控过程可能会为包括人类在内的高等真核生物的研究指明方向。公共卫生相关性：减数分裂过程中产生的非整倍体是人类智力低下和流产的主要原因。因此，确定控制减数分裂染色体分离的分子机制和确保配子准确形成的监测途径，对于理解染色体错误分离导致唐氏综合症和不育症的潜在原理至关重要。我们研究的长期目标是在分子水平上确定控制减数分裂染色体分离和配子形成的机制。

DESCRIPTION (provided by applicant): Aneuploidy is the leading cause of miscarriages and mental retardation in humans. Determining the causes of meiotic chromosome mis-segregation is thus vital for understanding the principles underlying Down's Syndrome and infertility. The long- term goal of our studies is to define the mechanisms that prevent chromosome mis-segregation and thus aneuploidy during meiosis. Meiosis is a specialized cell division during which a single DNA replication phase is followed by two consecutive chromosome segregation phases (meiosis I and meiosis II). Meiosis-specific factors act on the cyclin-dependent kinase (CDK) Cdc28 associated with the six Clb cyclins (Clb-CDKs) to bring about the unique meiotic cell division program. This grant has two goals. (1) We want to characterize how Clb-CDKs control meiosis. (2) We want to characterize the changes that occur on CDKs and its regulators during meiosis and to identify the meiosis-specific regulators that cause these changes. In Specific Aim 1 we will determine the mechanisms that prevent Clb1-CDKs from being active during meiosis II and examine the importance of this regulation. In Specific Aim 2 we will investigate how translation of the cyclin CLB3 is controlled. Inhibition of CLB3 translation is essential for meiosis I chromosome segregation. Thus, understanding how CLB3 translation is controlled and how CLB3 inhibits meiosis I is essential to understand how a meiosis I chromosome segregation pattern is established. In Specific Aim 3 we will determine how CLB3 inhibits meiosis I chromosome segregation. Since the basic cell division machinery is highly conserved from yeast to human and given that most of the factors described in this proposal have also been shown to control meiosis in mammals, it is likely that the processes governing meiosis will also be conserved across species. Thus, as with many other cell cycle studies, the regulatory processes discovered and characterized in yeast will likely guide the way for studies in higher eukaryotes including human. Public Health Relevance: Aneuploidy generated during meiosis is the leading cause of mental retardation and miscarriages in humans. Determining the molecular mechanisms governing meiotic chromosome segregation and the surveillance pathways that ensure that gamete formation occurs with accuracy is thus vital for understanding the principles underlying chromosome mis-segregation leading to Down's Syndrome and infertility. The long-term goal of our studies is to define the mechanisms that control meiotic chromosome segregation and gamete formation at the molecular level.