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Regulation of gene expression by transcriptional coactivators (COACTIVATOR)
Date du début: 1 déc. 2013, Date de fin: 30 nov. 2017 PROJET  TERMINÉ 

"How a cell responds to developmental or environmental changes by altering gene expression is a fundamental question in biology. Onecritical level of regulation is transcription initiation, which is controlled by large multiprotein complexes, including coactivators. Many studieshave shown that coactivators have distinct activities that play crucial roles in transcription, and their perturbation can cause cancer orneurodegeneration. Little is known, however, about how these activities integrate external signals to control transcription. I haveestablished one such coactivator, the highly conserved SAGA complex, as an excellent model to address this question. First, I discoveredthat, in the fission yeast Schizosaccharomyces pombe, SAGA regulates the switch from proliferation to differentiation. SAGA uses distinctactivities to function either as a repressor or as an activator of differentiation genes, depending on the levels of extracellular nutrients.Second, I discovered that S. pombe provides a unique opportunity to study the function of the largest SAGA subunit, Tra1. Its mammalianhomolog, TRRAP, is a key regulator of early embryogenesis and oncogenesis. My overall objective is to address key issues in theregulation of gene expression by focusing on SAGA, using a combination of genetic, genomic, biochemical, and proteomic approaches.One goal of this proposal is to identify which nutrient-sensing signaling pathway causes SAGA to switch from a repressor to an activator atthe promoters of differentiation genes. A second objective is to address the role of Tra1 in coordinating the activity of kinases sensingvarious cellular stresses and the regulatory roles of transcriptional coactivators. Overall, these studies will illuminate previously unknownmechanisms for the control of transcription by signal transduction pathways in eukaryotes."