Function and regulation of the Spt-Ada-Gcn5-Acetyltransferase (SAGA) deubiquitinase module

Cornelio-Parra, Dayanne V; Goswami, Rituparna; Costanzo, Kara; Morales-Sosa, Pedro; Mohan, Ryan D.

doi:10.1016/j.bbagrm.2020.194630

Cited by 9 publications

(11 citation statements)

References 105 publications

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“…USP22 is associated with the regulation of gene expression, cell growth, the cell cycle, regulation of complexes important for cytoskeleton dynamics, maintenance of cell identity, non-homologous end joining, immune responses, cancer, blindness, diabetes, male infertility, and neurodegenerative diseases [66,[159][160][161][162]. It is a component of the Spt-Ada-Gcn5-Acetyltransferase (SAGA) complex, which contains two enzymatic subunits-the GCN5 acetyltransferase and the USP22 deubiquitinase-housed in separate modules.…”

Section: Usp22mentioning

confidence: 99%

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Deubiquitinases in Neurodegeneration

Bello

Goswami

Brown

et al. 2022

Cells

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Ubiquitination refers to the conjugation of the ubiquitin protein (a small protein highly conserved among eukaryotes) to itself or to other proteins through differential use of ubiquitin’s seven internal linkage sites or the amino-terminal amino group. By creating different chain lengths, an enormous proteomic diversity may be formed. This creates a signaling system that is central to controlling almost every conceivable protein function, from proteostasis to regulating enzyme function and everything in between. Protein ubiquitination is reversed through the activity of deubiquitinases (DUBs), enzymes that function to deconjugate ubiquitin from itself and protein substrates. DUBs are regulated through several mechanisms, from controlled subcellular localization within cells to developmental and tissue specific expression. Misregulation of DUBs has been implicated in several diseases including cancer and neurodegeneration. Here we present a brief overview of the role of DUBs in neurodegeneration, and as potential therapeutic targets.

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Section: Usp22mentioning

confidence: 99%

“…USP22 contributes to the activation of gene expression by deubiquitinating histones, particularly monoubiquitinated H2B [164]. USP22-initiated deubiquitination of H2B is associated with increased transcription of multiple genes; however, the role of USP22-mediated deubiquitination of H2A is less clear [66,[160][161][162].…”

Section: Usp22mentioning

confidence: 99%

Deubiquitinases in Neurodegeneration

Bello

Goswami

Brown

et al. 2022

Cells

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“…As mentioned above, within SAGA, ATXN7 serves to anchor the deubiquitinase module to the larger SAGA complex. ATXN7 is oriented such that the amino-terminus of ATXN7, which is subject to polyglutamine expansion, extends into and intertwines among the three DUBm subunits ENY2 transcription and export complex 2 subunit (ENY2), ATXN7L3, and ubiquitin specific peptidase (USP) 22 (USP22) ( Cornelio-Parra et al, 2020 ). ENY2 and ATXN7L3 form a dimer, to which USP22, USP51, or USP27X can interchangeably dock, triggering their enzymatic activities ( Atanassov et al, 2016 ).…”

Section: Atxn7 Function Within the Spt Ada Gcn5 Acetyltransferase Chr...mentioning

confidence: 99%

The Molecular Basis of Spinocerebellar Ataxia Type 7

et al. 2022

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Spinocerebellar ataxia (SCA) type 7 (SCA7) is caused by a CAG trinucleotide repeat expansion in the ataxin 7 (ATXN7) gene, which results in polyglutamine expansion at the amino terminus of the ATXN7 protein. Although ATXN7 is expressed widely, the best characterized symptoms of SCA7 are remarkably tissue specific, including blindness and degeneration of the brain and spinal cord. While it is well established that ATXN7 functions as a subunit of the Spt Ada Gcn5 acetyltransferase (SAGA) chromatin modifying complex, the mechanisms underlying SCA7 remain elusive. Here, we review the symptoms of SCA7 and examine functions of ATXN7 that may provide further insights into its pathogenesis. We also examine phenotypes associated with polyglutamine expanded ATXN7 that are not considered symptoms of SCA7.

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“…SAGA is a 2MDa complex consisting of approximately 20 proteins structurally divided into modules with discrete biochemical functions (Grant et al, 1997; Roberts & Winston, 1997; Grant et al, 1998; Ben‐Shem et al, 2020; Cheon et al, 2020; Soffers & Workman, 2020; Grant et al, 2021; Helmlinger et al, 2021). As we and others have shown, these modules include an activator‐docking module comprising the TRRAP subunit, a core module that mediates recruitment of TATA‐binding protein (TBP) (Sharov et al, 2017; Papai et al, 2020; Wang et al, 2020), an acetyltransferase module (HAT), and a deubiquitylase module (DUB) (Brownell et al, 1996; McMahon et al, 1998; Henry et al, 2003; Cornelio‐Parra et al, 2021). The role of the acetyltransferase module has been extensively studied, and its catalytic subunit GCN5/KAT2A was the first KAT to be directly linked to transcription via acetylation of histones (Georgakopoulos & Thireos, 1992; Brownell et al, 1996; Grant et al, 1997), which leads to recruitment of the chromatin remodeler SWI/SNF (Chandy et al, 2006) and the super‐elongation complex (Gates et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

The SAGA complex regulates early steps in transcription via its deubiquitylase module subunit USP22

et al. 2021

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The SAGA coactivator complex is essential for eukaryotic transcription and comprises four distinct modules, one of which contains the ubiquitin hydrolase USP22. In yeast, the USP22 ortholog deubiquitylates H2B, resulting in Pol II Ser2 phosphorylation and subsequent transcriptional elongation. In contrast to this H2B‐associated role in transcription, we report here that human USP22 contributes to the early stages of stimulus‐responsive transcription, where USP22 is required for pre‐initiation complex (PIC) stability. Specifically, USP22 maintains long‐range enhancer–promoter contacts and controls loading of Mediator tail and general transcription factors (GTFs) onto promoters, with Mediator core recruitment being USP22‐independent. In addition, we identify Mediator tail subunits MED16 and MED24 and the Pol II subunit RBP1 as potential non‐histone substrates of USP22. Overall, these findings define a role for human SAGA within the earliest steps of transcription.

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Function and regulation of the Spt-Ada-Gcn5-Acetyltransferase (SAGA) deubiquitinase module

Cited by 9 publications

References 105 publications

Deubiquitinases in Neurodegeneration

Deubiquitinases in Neurodegeneration

The Molecular Basis of Spinocerebellar Ataxia Type 7

The SAGA complex regulates early steps in transcription via its deubiquitylase module subunit USP22

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