The mechanism by which eukaryotic genes are activated is inextricably linked with the packaging of DNA into chromatin. Coactivator complexes with histone-modifying activities play essential roles in this process by altering chromatin dynamics and interactions. Although there have been major advances in a molecular understanding many of the key macromolecular machines involved in eukaryotic transcription, progress in understanding coactivator function has lagged due to limited structural information on these large complexes and their interactions with chromatin. The SAGA coactivator is a 19-protein complex that has served as a paradigm for understanding the regulation of eukaryotic transcription and the connection between histone modifications and gene activation. SAGA deubiquitinates histone H2B, acetylates histone H3, and plays multiple roles in promoting transcription initiation and elongation. We have made substantial progress in our structural and biochemical studies of the SAGA deubiquitinating subcomplex and its interactions with ubiquitinated nucleosomes, as well as in our studies of Ubp10, a second H2B deubiquitinating enzyme, and of the interplay between histone chaperone activity and H2B deubiquitination. We will extend our studies to the full SAGA complex, determining the structure of SAGA bound to nucleosomes containing the relevant ubiquitin and methyl-lysine modifications by the method of cryo-electron microscopy. The resulting insights will reveal how the SAGA complex interfaces with the other components of the transcriptional machinery and will shed light on the mechanism by which histone ubiquitination, acetylation and methylation are manipulated to facilitate transcription through chromatin templates.
Disregulation of SAGA is implicated in human disease; overexpression of USP22, human homologue yeast Ubp8, is a signature of cancers for which there is no effective treatment while ATXN7, homologue of yeast Sgf73, is the effected protein in glutamine expansion disease, Spinocerebellar Ataxia Type 7. Insights from our structural studies of the yeast SAGA complex can be exploited to devise new therapies targeting human SAGA.
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| Jbara, Muhammad; Laps, Shay; Morgan, Michael et al. (2018) Palladium prompted on-demand cysteine chemistry for the synthesis of challenging and uniquely modified proteins. Nat Commun 9:3154 |
| Morrow, Marie E; Morgan, Michael T; Clerici, Marcello et al. (2018) Active site alanine mutations convert deubiquitinases into high-affinity ubiquitin-binding proteins. EMBO Rep 19: |
| Morgan, Michael T; Wolberger, Cynthia (2017) Recognition of ubiquitinated nucleosomes. Curr Opin Struct Biol 42:75-82 |
| Ringel, Alison E; Wolberger, Cynthia (2016) Structural basis for acyl-group discrimination by human Gcn5L2. Acta Crystallogr D Struct Biol 72:841-8 |
| Morgan, Michael T; Haj-Yahya, Mahmood; Ringel, Alison E et al. (2016) Structural basis for histone H2B deubiquitination by the SAGA DUB module. Science 351:725-8 |
| Jbara, Muhammad; Maity, Suman Kumar; Morgan, Michael et al. (2016) Chemical Synthesis of Phosphorylated Histone H2A at Tyr57 Reveals Insight into the Inhibition Mode of the SAGA Deubiquitinating Module. Angew Chem Int Ed Engl 55:4972-6 |
| Kumar, Pankaj; Magala, Pearl; Geiger-Schuller, Kathryn R et al. (2015) Role of a non-canonical surface of Rad6 in ubiquitin conjugating activity. Nucleic Acids Res 43:9039-50 |
| Kumar, Pankaj; Wolberger, Cynthia (2015) Structure of the yeast Bre1 RING domain. Proteins 83:1185-90 |
| Ringel, Alison E; Cieniewicz, Anne M; Taverna, Sean D et al. (2015) Nucleosome competition reveals processive acetylation by the SAGA HAT module. Proc Natl Acad Sci U S A 112:E5461-70 |
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