Molecular Mechanisms of Cell Cycle Control

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ABSTRACT Regulated progression through the cell division cycle is critical for cells to faithfully grow and divide. When cell cycle control is disrupted, cells can acquire mutations or proliferate uncontrollably, and this can lead to the development of diseases such as cancer. To ensure that cells replicate and divide accurately, multiple overlapping mechanisms function to coordinate and order cell cycle events. The focus of my laboratory is to understand how cell cycle-regulated transcription, phosphorylation and ubiquitin-mediated protein degradation are integrated to generate a robust cell cycle-regulatory network. To accomplish this we take advantage of high-throughput genetic approaches in budding yeast to uncover the systems-level consequences of perturbing cell cycle-regulatory genes. In this proposal we will focus on three key unanswered questions. First, how does phosphorylation of cell cycle-regulatory transcription factors (TFs) contribute to cell cycle control? We will utilize genetic interaction screens with phosphodeficient TF alleles to elucidate the importance of phosphorylation and test the hypothesis that TF phosphorylation is important to coordinate growth and energy production with the cell cycle. Second, how do stress response pathways cooperate to regulate the cell cycle in response to environmental stress? We will dissect the mechanism of crosstalk between conserved stress response pathways and investigate the importance of this crosstalk for cell cycle arrest and survival in response to distinct environmental stressors. Third, how do deubiquitinating enzymes (DUBs) regulate the stabilities of cell cycle-regulatory proteins? We will utilize an approach that we developed for identifying DUB substrates to investigate the in vivo functions of these enzymes and the mechanisms by which they control the cell cycle. By answering these questions, we will develop a network-level view of how transcription and proteolysis coordinate cell cycle events to ensure faithful cell division. Given the strong conservation between the cell cycle-regulatory mechanisms in yeast and human cells, we anticipate this work will provide insight into how disruptions in the cell cycle control network contribute to disease.