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Disruption of SAGA by polyglutamine-expanded Ataxin-7 and functional characterization of SAGA subunit Sgf29

Burke, Tara Lynne
Thesis/Dissertation; Online
Burke, Tara Lynne
Smith, Mitch
Grant, Patrick
Smith, Jeffrey
Auble, David
The conserved and multi-subunit SAGA complex exhibits multiple chromatinmodifying activities that play various roles in transcriptional regulation within the eukaryotic cell. SAGA subunits have been shown to serve numerous functions including providing complex structural integrity, optimizing and directing SAGA acetyltransferase and/ or deubiquitinase activity, and recruitment of basal transcription factors. With 20+ subunits, understanding the role each subunit contributes to the distinct functions of SAGA is an enormous task (Baker, Grant 2007). This dissertation focuses on understanding the role of two subunits, Ataxin-7 and Sgf29. Polyglutamine expansion of Ataxin-7 causes the autosomal dominant disorder spinocerebellar ataxia type-7 (SCA7). Our Ataxin-7 studies examine how polyglutamine expansion of this protein causes aberrant interactions within the complex, which lead to disruption ofnormal SAGA function. We demonstrate a direct inhibition of the acetyltransferase activity of Gcn5 in the presence of this mutant form of Ataxin7. Additionally, we characterize the role ofa lesser-known SAGA subunit, Sgf29. We find that Sgf29 contains two tandem Tudor domains that selectively interact with methylation marks on histone H3, lysine 4. This ability of Sgf29 to read specific modifications, in turn, is important for proper SAGA localization and acetylation in viva. Together, these two studies contribute to the development ofa comprehensive understanding of the multiple roles of SAGA during transcription and provide a molecular explanation ofhow SAGA mutation may lead to disease. Note: Abstract extracted from PDF file via OCR
University of Virginia, Department of Biochemistry and Molecular Genetics, PHD (Doctor of Philosophy), 2012
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PHD (Doctor of Philosophy)
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