Structural basis for histone H2B deubiquitination by the SAGA DUB module

Morgan, Michael T.; Haj‐Yahya, Mahmood; Ringel, Alison E.; Bandi, Prasanthi; Brik, Ashraf; Wolberger, Cynthia

doi:10.1126/science.aac5681

Cited by 228 publications

(313 citation statements)

References 48 publications

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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%

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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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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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“…In this line, Schulze and colleagues demonstrated that Ubp8 deubiquitinates H2BK123ub 1 at H3K4me 3 -marked regions (Schulze et al, 2011). Indeed, recent studies have revealed that the DUBm subunit, Sgf11 ZnF domain targets the nucleosome core particle (NPC) acidic patch (Morgan et al, 2016 …”

Section: Mog1 Co-purifies With Components Of the Transcription Machinerymentioning

confidence: 86%

“…Recent research has proposed that the DUBm principally contacts H2A/H2B by the basic Sgf11-ZnF domain. In addition, these researchers also found that the DUBm deubiquitinates from either intact or disassembled nucleosomes suggesting that it is able to act at diverse points as RNA Pol II transcribes through chromatin (Morgan et al, 2016). In addition to the organization of the DUBm components for Ubp8 activation, some studies have reported that DUBm needs to be assembled into SAGA complex for its correct function.…”

Section: Dubm Function and Structurementioning

confidence: 99%

“…Several studies have provided insights into the crystal structure of the DUBm showing that the four components are remarkably intertwined (Köhler et al, 2010;Morgan et al, 2016;Samara et al, 2010). According to these studies, the DUBm contains the full Ubp8, Sgf11, Sus1 and an Sgf73 N-terminal fragment extending to either residue 96 (Köhler et al, 2010) or 104 (Samara et al, 2010 (Köhler et al, 2010).…”

Section: Dubm Function and Structurementioning

confidence: 99%

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