Ubiquitination and acetylation in gene activation
The 1.9 MDa yeast SAGA complex has been a paradigm for understanding the connection between histone modifications and gene activation as well as the cross-talk between different types of modifications. SAGA functions in a cascade of posttranslational modifications that begins with monoubiquitination of histone H2B-K123m which triggers methylation of histone H3-K4. The SAGA complex is recruited, where it deubiquitinates H2B, recognizes the H3K4 trimethyl mark and acetylates histone H3. The 19 SAGA subunits are conserved from yeast to humans and are organized into subcomplexes including the four-protein SAGA deubiquitinating module (DUBm) and the four-protein SAGA histone acetyltransferase (HAT) module. Our structural and biochemical studies are aimed at uncovering how SAGA recognizes its nucleosomal substrates and how the multiple histone modifying activities of SAGA are coordinated during the process of gene activation. We are also using the insights from our structural studies to identify highly specific inhibitors of the SAGA deubiquitinating module.
Publications
Morgan M, Ikenoue T, Suga H, Wolberger C. (2022) Potent macrocycle inhibitors of the human SAGA deubiquitinating module. Cell Chem Biol. 29(4):544-554.e4. doi: 10.1016/j.chembiol.2021.12.004.
Morgan, Haj-Yahya, Ringel, Bandi, Brik, Wolberger (2016) Structural basis for histone H2B deubiquitination by the SAGA DUB module. Science 351: 725-8. PubMed
Ringel, Cieniewicz, Taverna, Wolberger (2015) Nucleosome competition reveals processive acetylation by the SAGA HAT module. PNAS 6;112(40):E5461-70. PubMed
Samara, Ringel, Wolberger (2012) A role for intersubunit interactions in maintaining SAGA deubiquitinating module structure and activity. Structure 20:1414-24. PubMed
Samara, Datta, Berndsen, Zhang, Yao, Cohen, Wolberger C. (2010) Structural insights into the assembly and function of the SAGA deubiquitinating module. Science 328: 1025-9. PubMed