Thursday, November 21, 2024
11/21/2024
Project Summary The goals of this proposal are to investigate fundamental mechanisms of chromatin modifiers which, when perturbed, may create conditions that can lead to cancer and other diseases in humans. These studies will largely focus on chromatin remodeling complexes (e.g. Swi/Snf) and proteins which modify histones (e.g. methylation, phosphorylation) in response to transcription, cell signaling and metabolism. The Swi/Snf nucleosome-remodeling complex functions as a tumor suppressor. Recurrent mutations in Swi/Snf are found in many cancers. This proposal focuses on novel functions of Swi/Snf complexes in yeast and mammalian cells that may contribute to cancer development when lost. Many subunits of the mammalian Swi/Snf complex have alternative paralog subunits which occupy different versions. Importantly, depletion of multiple paralogs of specific subunits has been shown to be synthetic lethal in cancer cell lines suggesting potential therapeutic avenues. We will investigate the redundant and nonredundant functions of paralogous subunits starting with ARID1A/ARID1B and SMARCA2/SMARCA4 (alternative ATPase subunits). We have found that ARID1B (but not ARID1A) interacts with paraspeckle (ribonucleoprotein particle) components and regulates splicing. We will explore the mechanisms and functions of Swi/Snf interactions with paraspeckles. We have discovered that SMARCA2 bromodomain undergoes acetylation unlike its paralog SMARCA4. We will investigate how this modification affects the activities of SMARCA2-containing Swi/Snf complexes including their interactions with acetylated nucleosomes. In yeast we have found that Swi/Snf regulates a number of genes involved in sulfur amino acid metabolism (The MET regulon). We will investigate the role of Swi/Snf in controlling the transcription factor Met4 and the MET regulon in general which is of particular interest due to the role of Met4 and the MET regulon in regulating cellular processes such as redox homeostasis, methylation, phospholipid metabolism, protein synthesis and cell cycle progression. Our discovery that the mammalian SETD2 methyltransferase interacts with RNA processing proteins (e.g. hnRNPL) has led us to investigate how these interactions regulate histone methylation during transcription and RNA splicing and processing. Finally, in yeast we discovered a nutrient sensing signaling pathway combining the CK2 and AMPK pathways to converge on the Tda1 kinase which phosphorylates histone H3T11 and activates stress responsive genes. Proposed studies will investigate regulation of Tda1, the functions of H3T11 phosphorylation in gene activation and whether this nutrient sensing pathway is conserved in mammals.
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