The human TREX-2 complex is stably associated with the nuclear pore basket

Umlauf, David; Bonnet, Jacques; Waharte, François; Fournier, Marjorie; Stierlé, Matthieu; Fischer, Benoit; Brino, Laurent; Devys, Didier; Tora, Làszlò

doi:10.1242/jcs.118000

Cited by 115 publications

(149 citation statements)

References 57 publications

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“…This result provides a plausible explanation for the decreased levels of ATXN7L3 protein level observed after overexpression of ATXN7L3B (Fig. 3A and B), as previous studies have shown that ENY2 is necessary for stabilization of ATXN7L3 (17,20). Overexpression of ATXN7L3B likely sequesters ENY2, resulting in less ENY2-ATXN7L3 association and destabilization of ATXN7L3.…”

Section: Resultssupporting

confidence: 68%

“…Examination of our MudPIT results indicates only a weak interaction of FH-ATXN7L3B with CETN2 (Fig. 1D), with no evidence for interaction with other TREX-2 components, including PCID2, DSS1, GANP, and CETN3 (20). We were not able to confirm interaction between ATXN7L3B and CETN2 by im-munoprecipitation, further suggesting that ATXN7L3B does not associate with TREX-2.…”

Section: Resultsmentioning

confidence: 74%

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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: Resultssupporting

confidence: 68%

Section: Resultsmentioning

confidence: 74%

Cytoplasmic ATXN7L3B Interferes with Nuclear Functions of the SAGA Deubiquitinase Module

Atanassov

Lan

et al. 2016

Molecular and Cellular Biology

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“…Tpr is thought to be the central architectural element of the nuclear basket (Krull et al, 2004) and is lately recruited during NPC reassembly (Bodoor et al, 1999;Haraguchi et al, 2000). Consistently, Nup153 localization to the NPC is not Tpr dependent (Frosst et al, 2002;Hase and Cordes, 2003), whereas the importance of Nup153 for Tpr recruitment is controversial: Nup153 depletion lead to a complete absence of Tpr from the NE on the one hand (Hase and Cordes, 2003), but not in other cases (Lussi et al, 2010;Mackay et al, 2010;Umlauf et al, 2013). In contrast to that, it is without any doubt that the association of Nup50 with NPCs necessitates the presence of Nup153 (Hase and Cordes, 2003;Mackay et al, 2010).…”

Section: Nup153 Assembly Into Nuclear Poresmentioning

confidence: 99%

The nuclear pore complex: structure and function

Duhéron¹,

Fahrenkrog²

2017

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Forkhead box P3 (FOXP3), a gene member of the forkhead/winged-helix family of transcription regulators, is Nuclear pore complexes (NPCs) are large multi-protein complexes, which are embedded in the nuclear envelope and which are regulating the molecular exchange between the nucleus and the cytoplasm. While electron microscopy and cryo-electron tomography studies have provided high-resolution pictures of the NPC structure as entity, the challenge nowadays is to elucidate the organization and the functions of nuclear pore proteins (nucleoporins or Nups) inside and outside the NPC. Nucleoporins are not only involved in nucleocytoplasmic transport, but in an increasing number of other cellular processes, such as kinetochore organization, cell cycle regulation, DNA repair, and gene expression. The implication of nucleoporins in these diverse processes links them also to a wide variety of human diseases, such as cancer and autoimmune diseases. Here we review the progress made in defining the molecular arrangement of nucleoporins within the NPC and use the example of Nup153 to illustrate the versatility of individual nucleoporins and their implication in various human diseases.

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“…In particular, the SAGA/TREX complex has been shown in both mammalian cells, Drosophila and nematodes to mediate transcriptional activation at the pores via interaction with nuclear basket proteins in a number of other organisms. 46,55,56 Third, since the X chromosome in hermaphrodites is 2-fold downregulated and not completely silent, two mechanisms linking DCC loading and transcriptional downregulation could be envisioned. In a first static scenario, the DCC remains stably associated with the X chromosome in hermaphrodites and does not allow association with nuclear pores, impairing transcriptional upregulation while allowing transcription.…”

Section: Open Questions and Considerations With The Modelmentioning

confidence: 99%

Linking dosage compensation and X chromosome nuclear organization inC. elegans

Sharma

Meister

2015

Nucleus

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A nimal sex is determined by the number of X chromosomes in many species, creating unequal gene dosage (aneuploidy) between sexes. Dosage Compensation mechanisms equalize this dosage difference by regulating X-linked gene expression. In the nematode C. elegans the current model suggests that DC is achieved by a 2-fold transcriptional downregulation in hermaphrodites mediated by the Dosage Compensation Complex (DCC), which restricts access to RNA Polymerase II by an unknown mechanism. Taking a nuclear organization point of view, we showed that the male X chromosome resides in the pore proximal subnuclear compartment whereas the DCC bound to the X, inhibits this spatial organization in the hermaphrodites. Here we discuss our results and propose a model that reassigns the role of DCC from repression of genes to inhibition of activation.

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The human TREX-2 complex is stably associated with the nuclear pore basket

Cited by 115 publications

References 57 publications

Cytoplasmic ATXN7L3B Interferes with Nuclear Functions of the SAGA Deubiquitinase Module

Cytoplasmic ATXN7L3B Interferes with Nuclear Functions of the SAGA Deubiquitinase Module

The nuclear pore complex: structure and function

Linking dosage compensation and X chromosome nuclear organization inC. elegans

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