Separation of a functional deubiquitylating module from the SAGA complex by the proteasome regulatory particle

Lim, Sungsu; Kwak, Jaechan; Kim, Minhoo; Lee, Daeyoup

doi:10.1038/ncomms3641

Cited by 37 publications

(36 citation statements)

References 66 publications

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“…In principal, SAGA may release subcomplexes to participate in diverse functions. It was recently shown in S. cerevisiae that the proteasome is capable of pulling the enzymatically active DUB module, including Sgf73, Sgf11, and Sus1, from SAGA, indicating that separation of SAGA may normally occur (Lim et al 2013). Further investigation into the modularity of SAGA and its implications for transcriptional regulation in vivo may aid in understanding how this complex might provide a sophisticated mechanism for chromatin modification and gene regulation.…”

Section: Loss Of Ataxin-7 Reduces H2b Ubiquitination Genes and Developmmentioning

confidence: 99%

Loss of Drosophila Ataxin-7, a SAGA subunit, reduces H2B ubiquitination and leads to neural and retinal degeneration

et al. 2014

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The Spt-Ada-Gcn5-acetyltransferase (SAGA) chromatin-modifying complex possesses acetyltransferase and deubiquitinase activities. Within this modular complex, Ataxin-7 anchors the deubiquitinase activity to the larger complex. Here we identified and characterized Drosophila Ataxin-7 and found that reduction of Ataxin-7 protein results in loss of components from the SAGA complex. In contrast to yeast, where loss of Ataxin-7 inactivates the deubiquitinase and results in increased H2B ubiquitination, loss of Ataxin-7 results in decreased H2B ubiquitination and H3K9 acetylation without affecting other histone marks. Interestingly, the effect on ubiquitination was conserved in human cells, suggesting a novel mechanism regulating histone deubiquitination in higher organisms. Consistent with this mechanism in vivo, we found that a recombinant deubiquitinase module is active in the absence of Ataxin-7 in vitro. When we examined the consequences of reduced Ataxin-7 in vivo, we found that flies exhibited pronounced neural and retinal degeneration, impaired movement, and early lethality.

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Section: Loss Of Ataxin-7 Reduces H2b Ubiquitination Genes and Developmmentioning

confidence: 99%

Loss of Drosophila Ataxin-7, a SAGA subunit, reduces H2B ubiquitination and leads to neural and retinal degeneration

et al. 2014

View full text Add to dashboard Cite

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“…Relevant to this issue, studies have already reported that the DUB module can interact with non-SAGA complexes. Under wild-type conditions in yeast, the proteasome chaperones interact with the Ubp8 and Sgf73 and separate them from SAGA (Lim et al 2013). The yeast DUB module subunit Sus1 is also present in the mRNA export complex TREX-2 (Rodriguez- Navarro et al 2004).…”

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

confidence: 99%

“…Notably, the DUB module can disassociate from SAGA under some conditions and remain stable. In yeast, a functional DUB module can be separated from SAGA by the proteasome regulatory particle (Lim et al 2013). In Drosophila, loss of the Sgf73 homolog Ataxin-7 leads to disassociation of an enzymatically active DUB module (Mohan et al 2014).…”

mentioning

confidence: 99%

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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“…Similarly, USP22 was shown to be active in vitro only when interacting with all subunits of the DUB module, including ATXN7L3, and was found to be fully active in vivo only as part of the SAGA complex (Lang et al 2011;Armour et al 2013). Although it was recently shown that the proteasome regulatory particle can separate a DUB module from the yeast SAGA complex in vitro, such a free DUB module has no apparent effect on the regulation of H2Bub in vivo (Lim et al 2013). In agreement with a role for SAGA in gene transcribed regions, different studies using ChIP on candidate genes previously suggested the recruitment of different SAGA subunits in gene bodies (Govind et al 2007; Wyce et al 2007), and genome-wide ChIP analyses in S. pombe and Drosophila embryos localized Gcn5 or Ada2b in the transcribed regions of a subset of expressed genes (Johnsson et al 2009;Weake and Workman 2012).…”

Section: Saga Acts On a Very Large Fraction Of Eukaryotic Genomesmentioning

confidence: 99%

The SAGA coactivator complex acts on the whole transcribed genome and is required for RNA polymerase II transcription

Bonnet¹,

Wang²,

Baptista³

et al. 2014

Genes Dev.

188

222

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The SAGA (Spt-Ada-Gcn5 acetyltransferase) coactivator complex contains distinct chromatin-modifying activities and is recruited by DNA-bound activators to regulate the expression of a subset of genes. Surprisingly, recent studies revealed little overlap between genome-wide SAGA-binding profiles and changes in gene expression upon depletion of subunits of the complex. As indicators of SAGA recruitment on chromatin, we monitored in yeast and human cells the genome-wide distribution of histone H3K9 acetylation and H2B ubiquitination, which are respectively deposited or removed by SAGA. Changes in these modifications after inactivation of the corresponding enzyme revealed that SAGA acetylates the promoters and deubiquitinates the transcribed region of all expressed genes. In agreement with this broad distribution, we show that SAGA plays a critical role for RNA polymerase II recruitment at all expressed genes. In addition, through quantification of newly synthesized RNA, we demonstrated that SAGA inactivation induced a strong decrease of mRNA synthesis at all tested genes. Analysis of the SAGA deubiquitination activity further revealed that SAGA acts on the whole transcribed genome in a very fast manner, indicating a highly dynamic association of the complex with chromatin. Thus, our study uncovers a new function for SAGA as a bone fide cofactor for all RNA polymerase II transcription.

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Separation of a functional deubiquitylating module from the SAGA complex by the proteasome regulatory particle

Cited by 37 publications

References 66 publications

Loss of Drosophila Ataxin-7, a SAGA subunit, reduces H2B ubiquitination and leads to neural and retinal degeneration

Loss of Drosophila Ataxin-7, a SAGA subunit, reduces H2B ubiquitination and leads to neural and retinal degeneration

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

The SAGA coactivator complex acts on the whole transcribed genome and is required for RNA polymerase II transcription

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