DNA Binding by Sgf11 Protein Affects Histone H2B Deubiquitination by Spt-Ada-Gcn5-Acetyltransferase (SAGA)

Koehler, Christian; Bonnet, Jacques; Stierlé, Matthieu; Romier, Christophe; Devys, Didier; Kieffer, Bruno

doi:10.1074/jbc.m113.500868

Cited by 24 publications

(23 citation statements)

References 35 publications

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“…Sgf11 is a Znf protein and can bind to nucleosomal DNA (Koehler et al 2014). Moreover, we found that Znf-binding sites are enriched in the Sgf11-specific targets (Supplemental Table S6).…”

Section: Dub and Hat Module Subunits Control Expression Of A Subset Omentioning

confidence: 75%

Enzymatic modules of the SAGA chromatin-modifying complex play distinct roles in Drosophila gene expression and development

Seidel

Szerszen

et al. 2017

Genes Dev.

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The Spt-Ada-Gcn5-acetyltransferase (SAGA) chromatin-modifying complex is a transcriptional coactivator that contains four different modules of subunits. The intact SAGA complex has been well characterized for its function in transcription regulation and development. However, little is known about the roles of individual modules within SAGA and whether they have any SAGA-independent functions. Here we demonstrate that the two enzymatic modules of Drosophila SAGA are differently required in oogenesis. Loss of the histone acetyltransferase (HAT) activity blocks oogenesis, while loss of the H2B deubiquitinase (DUB) activity does not. However, the DUB module regulates a subset of genes in early embryogenesis, and loss of the DUB subunits causes defects in embryogenesis. ChIP-seq (chromatin immunoprecipitation [ChIP] combined with high-throughput sequencing) analysis revealed that both the DUB and HAT modules bind most SAGA target genes even though many of these targets do not require the DUB module for expression. Furthermore, we found that the DUB module can bind to chromatin and regulate transcription independently of the HAT module. Our results suggest that the DUB module has functions within SAGA and independent functions.

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“…Sgf11 is a Znf protein and can bind to nucleosomal DNA (Koehler et al 2014). Moreover, we found that Znf-binding sites are enriched in the Sgf11-specific targets (Supplemental Table S6).…”

Section: Dub and Hat Module Subunits Control Expression Of A Subset Omentioning

confidence: 75%

Enzymatic modules of the SAGA chromatin-modifying complex play distinct roles in Drosophila gene expression and development

Seidel

Szerszen

et al. 2017

Genes Dev.

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“…A previous report by another group demonstrated that the ZnF-Sgf11 domain of ATXN7L3 is essential for DUB activity toward H2Bub1 in vitro (6). The ZnFSgf11 domain is also required for ATXN7L3 binding to nucleosomal DNA (11), and the crystal structure of the DUB module reveals that an arginine cluster in the ZnF-Sgf11 domain directly interacts with ubiquitinated nucleosomes and H2A/H2B heterodimer (12). Therefore, the absence of this domain in ATXN7L3B indicates that it is unlikely to interact with histones, consistent with our findings that the ATXN7L3B-DUB module cannot efficiently deubiquitinate histones in vitro and that ATXN7L3B is largely localized to the cytoplasm in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…The ZnF-Sgf11 domain of ATXN7L3 is essential for DUB activity toward H2Bub1 in vitro (6). The ZnF-Sgf11 domain is required for ATXN7L3 binding to nucleosomal DNA (11), and the crystal structure of the DUB module reveals that an arginine cluster in the ZnF-Sgf11 domain directly interacts with ubiquitinated nucleosomes and H2A/H2B heterodimer (12).…”

mentioning

confidence: 99%

Cytoplasmic ATXN7L3B Interferes with Nuclear Functions of the SAGA Deubiquitinase Module

Atanassov

Lan

et al. 2016

Molecular and Cellular Biology

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fThe SAGA complex contains two enzymatic modules, which house histone acetyltransferase (HAT) and deubiquitinase (DUB) activities. USP22 is the catalytic subunit of the DUB module, but two adaptor proteins, ATXN7L3 and ENY2, are necessary for DUB activity toward histone H2Bub1 and other substrates. ATXN7L3B shares 74% identity with the N-terminal region of ATXN7L3, but the functions of ATXN7L3B are not known. Here we report that ATXN7L3B interacts with ENY2 but not other SAGA components. Even though ATXN7L3B localizes in the cytoplasm, ATXN7L3B overexpression increases H2Bub1 levels, while overexpression of ATXN7L3 decreases H2Bub1 levels. In vitro, ATXN7L3B competes with ATXN7L3 to bind ENY2, and in vivo, knockdown of ATXN7L3B leads to concomitant loss of ENY2. Unlike the ATXN7L3 DUB complex, a USP22-ATXN7L3B-ENY2 complex cannot deubiquitinate H2Bub1 efficiently in vitro. Moreover, ATXN7L3B knockdown inhibits migration of breast cancer cells in vitro and limits expression of ER target genes. Collectively, our studies suggest that ATXN7L3B regulates H2Bub1 levels and SAGA DUB activity through competition for ENY2 binding. U SP22 and the SAGA deubiquitinase (DUB) module are important for normal embryonic development (1), and alterations in the expression or structure of component proteins are linked to neurodegenerative disease and cancer (2, 3). The DUB module consists of a catalytic subunit, USP22, and two adaptor proteins, ATXN7L3 and ENY2, required for deubiquitinase activity and stability of the DUB module (4-6). Another protein, ATXN7, functions as a bridge to integrate the core DUB module into the greater SAGA complex (7,8) and has also been reported to affect DUB activity (6, 9, 10).ATXN7L3 contains a Sus1/ENY2-binding region in its N-terminal region, a ZnF-Sgf11 domain, and a SCA7 domain in its C-terminal region (6). The presence of ATXN7L3 is essential for the deubiquitinase activity of the DUB module. No stable complex could be formed in the absence of ATXN7L3 (6). Moreover, the ZnF-Sgf11 domain of ATXN7L3 plays a pivotal role in the enzymatic activity, but is dispensable for the assembly, of the DUB module (6). The ZnF-Sgf11 domain of ATXN7L3 is essential for DUB activity toward H2Bub1 in vitro (6). The ZnF-Sgf11 domain is required for ATXN7L3 binding to nucleosomal DNA (11), and the crystal structure of the DUB module reveals that an arginine cluster in the ZnF-Sgf11 domain directly interacts with ubiquitinated nucleosomes and H2A/H2B heterodimer (12).Loss of ATXN7L3B, a paralog of ATXN7L3, may also be associated with neurodegenerative disease (13), as three family members exhibiting loss of chromosome region 12q21, where ATXN7L3B lies, exhibited motor and cognitive deficiencies, as well as learning difficulties and cerebellar ataxia. ATXN7L3B and ATXN7L3 share 74% identity within their N-terminal ϳ60 amino acid residues (Fig. 1A), including the Sus1/ENY2-binding region (Fig. 1A, in red) (6, 14). Interestingly, a truncated form of ATXN7L3 that only contains amino acids 3 to 76 was shown by others to ...

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“…Ubp8 is inactive until interacting with the other DUB module subunits, indicating that all four components are required for optimal enzymatic activity (Kö hler et al, 2008). The Sgf73 and Sgf11 subunits harbor the conserved SCA7 and Zinc finger domains, respectively, which have been shown to interact with nucleosomes (Bonnet et al, 2010;Koehler et al, 2014). The incorporation of a long polyglutamine expansion into ATXN7, the human homolog of Sgf73, leads to type 7 spinocerebellar ataxia (David et al, 1997;Helmlinger et al, 2004).…”

Section: Introductionmentioning

confidence: 97%

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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DNA Binding by Sgf11 Protein Affects Histone H2B Deubiquitination by Spt-Ada-Gcn5-Acetyltransferase (SAGA)

Cited by 24 publications

References 35 publications

Enzymatic modules of the SAGA chromatin-modifying complex play distinct roles in Drosophila gene expression and development

Enzymatic modules of the SAGA chromatin-modifying complex play distinct roles in Drosophila gene expression and development

Cytoplasmic ATXN7L3B Interferes with Nuclear Functions of the SAGA Deubiquitinase Module

Mapping the Deubiquitination Module within the SAGA Complex

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