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.
Keywords:
Gene Expression; Histone Acetylase; Histone Modification; Neurodegeneration; Polyglutamine Disease; Protein Complexes; Spinocerebellar Ataxia Type 7.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing / chemistry
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Ataxin-7
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DNA-Binding Proteins
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Galectins / chemistry
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Galectins / genetics
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Galectins / metabolism
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Histone Acetyltransferases / chemistry
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Histone Acetyltransferases / genetics
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Histone Acetyltransferases / metabolism
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Humans
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Nerve Tissue Proteins / chemistry*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Peptides / chemistry*
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Peptides / genetics
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Peptides / metabolism
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Protein Structure, Tertiary
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Saccharomyces cerevisiae / enzymology
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Saccharomyces cerevisiae / genetics
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Saccharomyces cerevisiae Proteins / chemistry
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Saccharomyces cerevisiae Proteins / genetics
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Saccharomyces cerevisiae Proteins / metabolism
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Spinocerebellar Ataxias / genetics
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Spinocerebellar Ataxias / metabolism
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Transcription Factors / chemistry
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Transcription Factors / genetics
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Transcription Factors / metabolism
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p300-CBP Transcription Factors / chemistry*
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p300-CBP Transcription Factors / genetics
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p300-CBP Transcription Factors / metabolism
Substances
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ATXN7 protein, human
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Adaptor Proteins, Signal Transducing
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Ataxin-7
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DNA-Binding Proteins
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Galectins
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LGALS7 protein, human
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Nerve Tissue Proteins
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Peptides
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Recombinant Proteins
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Saccharomyces cerevisiae Proteins
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TADA2A protein, human
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Transcription Factors
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polyglutamine
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GCN5 protein, S cerevisiae
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Histone Acetyltransferases
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p300-CBP Transcription Factors
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p300-CBP-associated factor