Direct Inhibition of Gcn5 Protein Catalytic Activity by Polyglutamine-expanded Ataxin-7

Burke, Terrence R.; Miller, J.; Grant, Patrick A.

doi:10.1074/jbc.m113.487538

Cited by 28 publications

(25 citation statements)

References 32 publications

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“…The human DUB module subunit Ataxin7 (orthologous to yeast Sgf73) contains a region that can undergo poly‐glutamine expansion, causing the disease spinocerebellar ataxia type 7. Human Ataxin7 can partially complement a SGF73 deletion, but the Poly Q form inhibits HAT activity in vivo and in vitro (McMahon et al , ; Palhan et al , ; Burke et al , ). Here, we have shown that mutations in the DUB module subunit Sgf73 have modest effects on SAGA nucleosomal HAT activity and stability of the HAT module within SAGA.…”

Section: Discussionmentioning

confidence: 99%

Architecture of the S accharomyces cerevisiae SAGA transcription coactivator complex

et al. 2014

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The conserved transcription coactivator SAGA is comprised of several modules that are involved in activator binding, TBP binding, histone acetylation (HAT) and deubiquitination (DUB). Crosslinking and mass spectrometry, together with genetic and biochemical analyses, were used to determine the molecular architecture of the SAGA-TBP complex. We find that the SAGA Taf and Taf-like subunits form a TFIID-like core complex at the center of SAGA that makes extensive interactions with all other SAGA modules. SAGA-TBP binding involves a network of interactions between subunits Spt3, Spt8, Spt20, and Spt7. The HAT and DUB modules are in close proximity, and the DUB module modestly stimulates HAT function. The large activator-binding subunit Tra1 primarily connects to the TFIID-like core via its FAT domain. These combined results were used to derive a model for the arrangement of the SAGA subunits and its interactions with TBP. Our results provide new insight into SAGA function in gene regulation, its structural similarity with TFIID, and functional interactions between the SAGA modules.

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Section: Discussionmentioning

confidence: 99%

Architecture of the S accharomyces cerevisiae SAGA transcription coactivator complex

et al. 2014

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“…In mammalian cells, the deletion of Gcn5 impairs the association of the DUB module with SAGA (Atanassov et al, 2009), while in yeast, the full deletion of Sgf73 compromises the HAT activity, which can be restored by expressing human ATXN7 (McMahon et al, 2005). Furthermore, an ATXN7 carrying a 60 glutamine repeat to mimic the human SCA7 disease was described to bind to a recombinant Gcn5/ada2/ada3 complex and to decrease its HAT activity (Burke et al, 2013). The spatial proximity of the HAT and DUB modules does not contradict this observation since a long and unstructured polyQ stretch could interfere with the HAT catalytic or regulatory activities or with the nucleosome recognition functions.…”

Section: Position Of the Dub Modulementioning

confidence: 96%

Mapping the Deubiquitination Module within the SAGA Complex

et al. 2014

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The molecular organization of the yeast transcriptional coactivator Spt-Ada-Gcn5 acetyltransferase (SAGA) was analyzed by single-particle electron microscopy. Complete or partial deletion of the Sgf73 subunit disconnects the deubiquitination (DUB) module from SAGA and favors in our conditions the cleavage of the C-terminal ends of the Spt7 subunit and the loss of the Spt8 subunit. The structural comparison of the wild-type SAGA with two deletion mutants positioned the DUB module and enabled the fitting of the available atomic models. The localization of the DUB module close to Gcn5 defines a chromatin-binding interface within SAGA, which could be demonstrated by the binding of nucleosome core particles. The TATA-box binding protein (TBP)-interacting subunit Spt8 was found to be located close to the DUB but in a different domain than Spt3, also known to contact TBP. A flexible protein arm brings both subunits close enough to interact simultaneously with TBP.

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“…Poly(Q) expansions in ATXN7 could affect either of these activities. Previous studies provided conflicting evidence regarding the effects of ATXN7-poly(Q) on the activity of Gcn5, the catalytic subunit of the histone acetyltransferase (HAT) module (8)(9)(10)(11). The loss of Gcn5 accelerates cerebellar Purkinje cell and retinal degeneration in a SCA7 mouse model, indicating that Gcn5 functions are pertinent to disease progression (12).…”

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confidence: 99%

Poly(Q) Expansions in ATXN7 Affect Solubility but Not Activity of the SAGA Deubiquitinating Module

Lan

Koutelou

Schibler

et al. 2015

Molecular and Cellular Biology

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c Spinocerebellar ataxia type 7 (SCA7) is a debilitating neurodegenerative disease caused by expansion of a polyglutamine [poly(Q)] tract in ATXN7, a subunit of the deubiquitinase (DUB) module (DUBm) in the SAGA complex. The effects of ATXN7-poly(Q) on DUB activity are not known. To address this important question, we reconstituted the DUBm in vitro with either wild-type ATXN7 or a pathogenic form, ATXN7-92Q NT, with 92 Q residues at the N terminus (NT). We found that both forms of ATXN7 greatly enhance DUB activity but that ATXN7-92Q NT is largely insoluble unless it is incorporated into the DUBm. Cooverexpression of DUBm components in human astrocytes also promoted the solubility of ATXN7-92Q, inhibiting its aggregation into nuclear inclusions that sequester DUBm components, leading to global increases in ubiquitinated H2B (H2Bub) levels. Global H2Bub levels were also increased in the cerebellums of mice in a SCA7 mouse model. Our findings indicate that although ATXN7 poly(Q) expansions do not change the enzymatic activity of the DUBm, they likely contribute to SCA7 by initiating aggregates that sequester the DUBm away from its substrates.

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Direct Inhibition of Gcn5 Protein Catalytic Activity by Polyglutamine-expanded Ataxin-7

Cited by 28 publications

References 32 publications

Architecture of the S accharomyces cerevisiae SAGA transcription coactivator complex

Architecture of the S accharomyces cerevisiae SAGA transcription coactivator complex

Mapping the Deubiquitination Module within the SAGA Complex

Poly(Q) Expansions in ATXN7 Affect Solubility but Not Activity of the SAGA Deubiquitinating Module

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