This project will explore the regulatory system that controls progression through the stages of the eukaryotic cell division cycle. Cell-cycle progression is governed by an important class of protein kinases called the cyclin- dependent kinases or Cdks. In the proposed studies, biochemical and molecular genetics approaches will be used in the budding yeast Saccharomyces cerevisiae to address the mechanisms by which Cdks control progression through the final stages of cell division - with an emphasis on the roles of protein substrates that are phosphorylated by Cdks in the cell. In the previous funding period, large numbers of candidate Cdk substrates were identified and characterized, and future work will address the function of selected targets in the control of two major processes: chromosome segregation in mitosis and cell division in cytokinesis.
The first aim centers on the Cdk substrate Eco1, which promotes the cohesion of sister chromatids as they are synthesized in S phase. Previous work revealed that Eco1 is inhibited after S phase by Cdk1-mediated phosphorylation, which triggers Eco1 destruction via the ubiquitin ligase SCF-Cdc4.
The first aim of the current proposal is to obtain a comprehensive understanding of Eco1 regulation by phosphorylation, both by Cdk1 and by another protein kinase, Cdc7, that was uncovered as an Eco1 regulator in preliminary studies.
The second aim of the proposed work will be to understand the regulatory mechanisms that control the initiation of cytokinesis, with a focus on how the dephosphorylation of several Cdk1 substrates helps govern the assembly and function of the contractile ring that drives the division of the cell. The information gained from these studies will provide important new insights into the control of cell-cycle progression, and will thereby enhance our understanding of diseases, such as cancer, in which cell-cycle control or chromosome segregation is defective.
When a cell reproduces, the chromosomes are first duplicated and then distributed into a pair of daughter cells. Errors in this process can result in genetic damage or defects in chromosome number, which can accelerate cancer progression or cause developmental defects. The proposed studies focus on a class of proteins, called cyclin-dependent kinases, that are the master regulators of the steps in cell division. These studies will lead to a better understanding of how errors in chromosome behavior and cell division can arise in human disease.
|Naylor, Stephen G; Morgan, David O (2014) Cdk1-dependent phosphorylation of Iqg1 governs actomyosin ring assembly prior to cytokinesis. J Cell Sci 127:1128-37|
|Lopez, Michael S; Choy, Jonathan W; Peters, Ulf et al. (2013) Staurosporine-derived inhibitors broaden the scope of analog-sensitive kinase technology. J Am Chem Soc 135:18153-9|
|Lyons, Nicholas A; Fonslow, Bryan R; Diedrich, Jolene K et al. (2013) Sequential primed kinases create a damage-responsive phosphodegron on Eco1. Nat Struct Mol Biol 20:194-201|
|Kõivomägi, Mardo; Valk, Ervin; Venta, Rainis et al. (2011) Cascades of multisite phosphorylation control Sic1 destruction at the onset of S phase. Nature 480:128-31|
|Lyons, Nicholas A; Morgan, David O (2011) Cdk1-dependent destruction of Eco1 prevents cohesion establishment after S phase. Mol Cell 42:378-89|
|Kõivomägi, Mardo; Valk, Ervin; Venta, Rainis et al. (2011) Dynamics of Cdk1 substrate specificity during the cell cycle. Mol Cell 42:610-23|
|Holt, Liam J; Tuch, Brian B; Villén, Judit et al. (2009) Global analysis of Cdk1 substrate phosphorylation sites provides insights into evolution. Science 325:1682-6|
|Blethrow, Justin D; Glavy, Joseph S; Morgan, David O et al. (2008) Covalent capture of kinase-specific phosphopeptides reveals Cdk1-cyclin B substrates. Proc Natl Acad Sci U S A 105:1442-7|
|Holt, Liam J; Krutchinsky, Andrew N; Morgan, David O (2008) Positive feedback sharpens the anaphase switch. Nature 454:353-7|
|Holt, Liam J; Hutti, Jessica E; Cantley, Lewis C et al. (2007) Evolution of Ime2 phosphorylation sites on Cdk1 substrates provides a mechanism to limit the effects of the phosphatase Cdc14 in meiosis. Mol Cell 25:689-702|
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