Causes and consequences of aneuploidy

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 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.