title: Direct inhibition of Gcn5 protein catalytic activity by polyglutamine-expanded ataxin-7.
abstract: Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease caused by polyglutamine (polyQ) expansion within the N-terminal region of the ataxin-7 protein, a known subunit of the SAGA complex. Although the mechanisms of SCA7 pathogenesis remain poorly understood, previous studies have shown perturbations in SAGA histone acetyltransferase function and transcriptional alterations. We sought to determine whether and how polyQ-expanded ataxin-7 affects SAGA catalytic activity. Here, we determined that polyQ-expanded ataxin-7 directly bound the Gcn5 catalytic core of SAGA while in association with its regulatory proteins, Ada2 and Ada3. This caused a significant decrease in Gcn5 histone acetyltransferase activity in vitro and in vivo at two SAGA-regulated galactose genes, GAL1 and GAL7. However, Gcn5 occupancy at the GAL1 and GAL7 promoters was increased in these cells, revealing a dominant-negative phenotype of the polyQ-expanded ataxin-7-incorporated, catalytically inactive SAGA. These findings suggest a dominant mechanism of polyQ-mediated SAGA inhibition that potentially contributes to SCA7 disease pathogenesis.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia 22908.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Burke
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia 22908.
authors.forename: Jaime L
authors.initials: JL
authors.lastname: Miller
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia 22908. Electronic address: pag9n@virginia.edu.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Grant
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000067719:Ataxin-7; D004268:DNA-Binding Proteins; D037161:Galectins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000099224:p300-CBP-Associated Factor
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000067719:Ataxin-7; D004268:DNA-Binding Proteins; D037161:Galectins; D051548:Histone Acetyltransferases; D009419:Nerve Tissue Proteins; D010455:Peptides; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C000593829:ATXN7 protein, human; C092525:LGALS7 protein, human; C097695:TADA2A protein, human; C097188:polyglutamine; C501392:GCN5 protein, S cerevisiae
keywords: Gene Expression; Histone Acetylase; Histone Modification; Neurodegeneration; Polyglutamine Disease; Protein Complexes; Spinocerebellar Ataxia Type 7