Causes and consequences of aneuploidy

 描述（由申请人提供）：非整倍性，一种不正确的染色体数目，对人类健康有深远的影响。它是人类流产和智力迟钝的主要原因，也是癌症的标志。我们研究的长期目标是确定防止配子发生过程中发生非整倍性的分子机制，以及不正确的核型对细胞生理和增殖的影响。 在我们的配子发生的工作中，我们专注于确定诱导生殖细胞命运的分子机制，并将经典的有丝分裂细胞周期转化为独特的减数分裂细胞分裂程序。真核生物中的配子细胞特化尚不清楚，但这一过程对有性生殖至关重要。我们将研究芽殖酵母中的生殖细胞命运特化，其中该细胞命运由转录因子Ime 1诱导。我们将研究多种信号是如何整合在IME 1启动子，以确保生殖细胞的命运只在适当的条件下诱导。我们还将研究将经典的有丝分裂细胞周期转化为独特的配子发生伴随减数分裂的机制。我们将研究如何不适当的过早表达的CDK亚型，Clb 3-CDK，抑制减数分裂I，而不是诱导有丝分裂。此外，我们将研究确保Clb 3-CDKs不过早表达的分子机制。我们以前的研究表明，抑制翻译阻止Clb 3在减数分裂I期间的表达。我们现在将确定减数分裂I翻译抑制的分子机制。从酵母到人类，配子发生和减数分裂的机制是高度保守的。因此，在酵母中发现和表征的调控过程将可能指导包括人类在内的高等真核生物的研究。 在我们关于非整倍体对细胞生理学的影响的工作中，我们关注不平衡的核型对细胞增殖和蛋白质质量控制的影响。我们以前在酵母中的研究揭示了许多不同的非整倍体之间共享的一组表型，我们称之为非整倍体相关应激。它们包括转录应激反应、细胞增殖缺陷、对能量的需求增加、基因组不稳定性和蛋白毒性应激。重要的是，我们在哺乳动物细胞中的研究表明，这些非整倍性相关的压力在真核生物中是保守的。我们现在将集中在两个非整倍体相关的表型和调查他们是如何连接。我们将确定非整倍体诱导的蛋白毒性的分子基础，以及它如何有助于非整倍体细胞的增殖缺陷。癌症是高度非整倍体的，并且处于深刻的蛋白毒性应激下。因此，确定哪些蛋白质质量控制途径在具有改变的核型的细胞中是脆弱的，以及这如何影响细胞增殖，与理解癌细胞的生理状态高度相关。

 DESCRIPTION (provided by applicant): Aneuploidy, an incorrect chromosome number, has a profound impact on human health. It is the leading cause of miscarriages and mental retardation in humans and a hallmark of cancer. The long-term goal of our studies is to define the molecular mechanisms that prevent the occurrence of aneuploidy during gametogenesis and the impact of an incorrect karyotype on cell physiology and proliferation. In our work on gametogenesis we focus on determining the molecular mechanisms that induce germ cell fate and that transform the canonical mitotic cell cycle into the unique meiotic cell division program. Gamete cell specification is poorly understood in all eukaryotes yet the process is so critical for sexual reproduction. We will study germ cell fate specification in budding yeast where this cell fate is induced by the transcription factor Ime1. We will investigate how multiple signals are integrated at the IME1 promoter to ensure that germ cell fate is only induced under the appropriate conditions. We will also examine the mechanisms that transform the canonical mitotic cell cycle into the unique gametogenesis-accompanying meiotic division. We will investigate how inappropriate premature expression of a CDK subtype, Clb3-CDK, suppresses meiosis I and instead induces a mitotic division. Furthermore we will study the molecular mechanisms that ensure that Clb3-CDKs are not expressed prematurely. Our previous studies showed that inhibition of translation prevents Clb3 expression during meiosis I. We will now determine the molecular mechanisms governing meiosis I translational inhibition. The mechanisms governing gametogenesis and meiosis are highly conserved from yeast to human. Thus, the regulatory processes discovered and characterized in yeast will likely guide the way for studies in higher eukaryotes including human. In our work on the consequences of aneuploidy on cell physiology we focus on the effects of an imbalanced karyotype on cell proliferation and protein quality control. Our previous studies in yeast revealed a set of phenotypes shared among many different aneuploidies, which we call the aneuploidy-associated stresses. They include a transcriptional stress response, a cell proliferation defect, increased need for energy, genome instability and proteotoxic stress. Importantly, our studies in mammalian cells revealed that these aneuploidy-associated stresses are conserved across eukaryotes. We will now focus on two aneuploidy- associated phenotypes and investigate how they are connected. We will determine the molecular basis for aneuploidy-induced proteotoxicity and how it contributes to the proliferation defects of aneuploid cells. Cancers are highly aneuploid and under profound proteotoxic stress. Determining which protein quality control pathways are vulnerable in cells with an altered karyotype and how this affects cell proliferation is thus highly relevant to understanding the physiological state of cancer cells.