Aaron P. Mitchell
Department of Biological Sciences
Carnegie Mellon University
4400 Fifth Avenue
Pittsburgh, PA 15213
Voice: 412-268-5844 (office); -3185 (lab)
1989 Searle Scholar
Control of Mitosis/Meiosis in Yeast
We are interested in how yeast cells decide to exit the mitotic cell cycle and enter meiosis. Our studies have led to the question of how a set of genes is expressed exclusively in meiotic cells. One central positive regulator of meiotic genes is IME1. IME1 transcription is stimulated by the same genetic and environmental signals that stimulate meiosis. The target DNA sequence through which IME1 stimulates meiotic gene transcription is a negative regulatory site in non-meiotic cells. Repression through the site requires a putative DNA binding protein called UME6. UME6 is also required for IME1 to activate meiotic gene expression. Thus we believe that IME1 modifies the UME6 repression complex to convert it to an activation complex. This model predicts that IME1 will have a transcriptional activation domain, which we have confirmed by constructing transcriptional activators through fusions of IME1 to the lexA DNA-binding domain. We are testing the predictions that IME1 and UME6 will bind to one another and that the IME1-UME6 complex will bind to DNA.
Only one type of cell (called an a/a cell) can enter meiosis; the other types of cells (a and a cells) cannot. An inhibitor of meiosis, called RME1, is expressed in a and a cells but not in a/a cells. RME1, a zinc-finger protein, blocks meiosis by repressing expression of IME1. RME1 binds to a site 2 Kbp upstream of the IME1 gene. Repression requires both the RME1 binding site and an adjacent 300 bp region. Our current aim is to identify the proteins that bind in this 300 bp region, to understand how they interact with RME1, and to explore the mechanism of repression over this large interval.
Once cells complete meiotic prophase, the earliest meiotic genes are shut off and a new set of genes is activated. The IME2 product, a protein kinase, is essential for this transition. Presence of chromosome pairs is also essential for this transition. We are now testing the hypothesis that IME2 kinase activity responds to a ploidy-dependent signal. These studies may have broad implications for the regulation of meiosis, because we have found a mouse homolog of IME2 that is expressed primarily in testes.
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