Regulation of the meiotic cell cycle

描述（由申请人提供）：非整倍体是人类流产和智力迟钝的主要原因。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基本原理至关重要。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，在此期间，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）。减数分裂特异性因子作用于与六种Clb细胞周期蛋白（Clb-CDKs）相关的细胞周期蛋白依赖性激酶（CDK）Cdc 28，以引起独特的减数分裂细胞分裂程序。这笔赠款有两个目标。(1)我们想要表征Clb-CDK如何控制减数分裂。(2)我们希望描述减数分裂过程中CDK及其调节因子发生的变化，并确定引起这些变化的减数分裂特异性调节因子。在具体目标1中，我们将确定阻止Clb 1-CDKs在减数分裂II期间活跃的机制，并研究这种调节的重要性。在具体目标2中，我们将研究细胞周期蛋白CLB 3的翻译是如何控制的。CLB 3翻译的抑制对于减数分裂I染色体分离是必不可少的。因此，了解CLB 3翻译是如何控制的，以及CLB 3如何抑制减数分裂I是至关重要的，以了解如何建立减数分裂I染色体分离模式。在具体目标3中，我们将确定CLB 3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都是高度保守的，并且鉴于本提案中描述的大多数因子也已被证明可以控制哺乳动物的减数分裂，因此很可能控制减数分裂的过程也将在物种之间保守。因此，与许多其他细胞周期研究一样，在酵母中发现和表征的调控过程可能会指导高等真核生物（包括人类）的研究。公共卫生相关性：减数分裂期间产生的非整倍体是人类智力迟钝和流产的主要原因。因此，确定减数分裂染色体分离的分子机制和确保配子形成准确发生的监视途径对于理解导致唐氏综合征和不育的染色体错误分离的基本原理至关重要。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.