Protein Interaction Domains of the Ubiquitin-specific Protease, USP7/HAUSP

Holowaty, Melissa N.; Sheng, Yi; Nguyen, Tin; Arrowsmith, C.H.; Frappier, Lori

doi:10.1074/jbc.m307200200

Cited by 161 publications

(173 citation statements)

References 39 publications

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“…By sequestering USP7, EBNA-1 may destabilize p53 with important consequences for both B-cell immortalization and the development of EBV-associated tumors. This possibility was recently substantiated by the demonstration that a synthetic peptide corresponding to residues 395-450 of EBNA-1 is able to compete with a p53 peptide for binding to USP7 (Holowaty et al, 2003a).…”

Section: The Rescue Program: Lmp-2a and The Capture Of Cellular Ubiqumentioning

confidence: 91%

Epstein–Barr virus oncogenesis and the ubiquitin–proteasome system

Masucci

2004

Oncogene

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Epstein-Barr virus (EBV), a human herpesvirus associated with lymphoid and epithelial cell tumors, encodes several proteins that exploit the ubiquitin-proteasome system to regulate latency and allow the persistence of infected cells in immunocompetent hosts. Further modifications of ubiquitin-dependent proteolysis by activated cellular oncogenes contribute to malignant transformation. A detailed understanding of these processes may lead to the development of new therapeutic strategies for EBVassociated cancers.

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Section: The Rescue Program: Lmp-2a and The Capture Of Cellular Ubiqumentioning

confidence: 91%

Epstein–Barr virus oncogenesis and the ubiquitin–proteasome system

Masucci

2004

Oncogene

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“…Moreover, the increased tumor induction that follows SCID mouse injection with EBV reinfected Akata Burkitt lymphoma cells is attributed to the EBV small RNAs and not to EBNA1 (55,56). Nevertheless, EBNA1 can interact with USP7, the p53 ubiquitin protease, and EBNA1 overexpression can inhibit p53-overexpression-mediated apoptosis (32,33,37).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, EBNA1 has little effect on transcription of an EBNA1-dependent reporter integrated at most sites in cell DNA (20,29). Alternatively, EBNA1 might alter cell growth or survival through an interaction with a cell protein (30)(31)(32)(33)(34)(35)(36)(37)(38)(39). However, once EBV DNA has integrated into cell DNA, EBNA1 is not required for LCL growth, and LCLs with EBNA1-null mutant EBV genomes are indistinguishable from wild-type EBV-transformed B lymphocytes in their growth (12).…”

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confidence: 99%

Epstein-Barr virus nuclear antigen 1 does not induce lymphoma in transgenic FVB mice

Kang

Yasui

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The lymphoma-inducing potential of Ig heavy-chain enhancer-and promoter-regulated Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) was evaluated in three transgenic FVB mouse lineages. EBNA1 was expressed at a higher level in transgenic B220(؉) splenocytes than in EBV-infected lymphoblastoid cell lines. EBNA1 was also expressed in B220(؊) transgenic splenocytes and thymocytes. Before killing and assessments at 18 -26 months, EBNA1-transgenic mice did not differ from control mice in mortality. At 18 -26 months EBNA1-transgenic mice did not differ from littermate control in ultimate body weight, in spleen size or weight, in lymph node, kidney, liver, or spleen histology, in splenocyte fractions positive for cluster of differentiation (CD)3 , CD4, CD8, CD62L, B220, CD5, IgM, IgD, MHC class II, CD11b, or CD25, or in serum IgM, IgG, or total Ig levels. Lymphomas were not found in spleens or other organs of 18-to 26-month-old EBNA1-transgenic (n ‫؍‬ 86) or control (n ‫؍‬ 45) FVB mice. EBNA1-transgenic lineages had a higher pulmonary adenoma prevalence than did littermate controls (39% versus 7%). However, the adenoma prevalence was not higher in EBNA1-transgenic mice than has been described for FVB mice, and EBNA1 was not expressed in normal pulmonary epithelia or adenomas.cancer ͉ herpesvirus ͉ latent ͉ persistence I n initial lymphocyte infection, Epstein-Barr Virus (EBV) causes B lymphocyte proliferation through a latency III program of expression of six nuclear proteins (EBNAs), two different integral membrane proteins, two small RNAs, and Bam A-initiated transcripts (1, 2). Although, in vitro, latency III-infected lymphocytes are able to grow endlessly as lymphoblastoid cell lines (LCLs), EBV proteins expressed in latency III-infected cells, in vivo, engender T cell responses that limit infected cell survival. EBV mostly persists long term in nonproliferating, latency I-or II-infected B cells that express EBNA1 or EBNA1 and latent infection membrane proteins, respectively (2-4). Latency I or latency II are also characteristic of Burkitt's lymphoma, Hodgkin's disease, and nasopharyngeal carcinoma (2). EBNA1 is expressed in almost all latent EBV infections and associated malignant diseases.EBNA1 enables efficient EBV episome replication, transcription, and maintenance in latently infected dividing cells (5-21). EBNA1 amino acids 379-641 include a dimerization and DNAbinding domain, which binds cognate 30-bp inverted repeat DNA sequences. EBV origin of plasmid replication (oriP) consists of 20 tandem cognate 30-bp repeats and four others 1 kbp away in a dyad symmetry (22). OriP has intrinsic origin activity. EBNA1 enhances oriP-dependent episome replication, transcription, and maintenance (7,8). EBNA1 amino acids 1-378 are necessary for chromosome association, transcriptional enhancement, and episome persistence, although not for initial DNA replication (21,(23)(24)(25). Within amino acids 1-378 is an irregular glycine͞alanine repeat, which inhibits EBNA1 processing through the proteasome͞TAP pathway (26,27).Becau...

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“…EBNA1 associates with multiple host proteins including ubiquitin-specific protease 7 (USP7), casein kinase 2 (CK2) (36,37), EBP2 and others (26,(37)(38)(39)(40)(41). The core interaction sites of EBNA1 with USP7 and CK2 have been determined and map to the central region of the protein (37,42).…”

Section: Introductionmentioning

confidence: 99%

Modelling the structure of full-length Epstein–Barr virus nuclear antigen 1

2014

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Abstract:Epstein-Barr virus (EBV) is a clinically important human virus associated with several cancers and is the etiologic agent of infectious mononucleosis. The viral nuclear antigen-1 (EBNA1) is central to the replication and propagation of the viral genome and likely contributes to tumourigenesis. We have compared EBNA1 homologues from other primate lymphocryptoviruses (LCV) and found that the central glycine/alanine repeat (GAr) domain, as well as predicted cellular protein (USP7 and CK2) binding sites are present in homologues in the Old World primates, but not the marmoset; suggesting that these motifs may have co-evolved. Using the resolved structure of the C-terminal one third of EBNA1 (homodimerisation and DNA binding domain), we have gone on to develop monomeric and dimeric models in silico of the full length protein.The C-terminal domain is predicted to be structurally highly similar between homologues, indicating conserved function. Zinc could be stably incorporated into the model, bonding with two N-terminal cysteines predicted to facilitate multimerisation. The GAr contains secondary structural elements in the models, while the protein binding regions are unstructured, irrespective of the prediction approach used and sequence origin. These intrinsically disordered regions may facilitate the diversity observed in partner interactions. We hypothsise that the structured GAr could mask the disordered regions, thereby protecting the protein from default degradation. In the dimer conformation, the C-terminal tails of each monomer wrap around a proline-rich protruding loop of the partner monomer, providing dimer stability, a feature which could be exploited in therapeutic design. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation EBV-B95-8 hu-EBNA1CyEBV-TsBB6 cy-EBNA1 CeHV15 rh-EBNA1CeHV12 ba-EBNA1 CalHV3 ma EBNA1Modelling the structure of full length Epstein-Barr Virus Nuclear Antigen Figure S2. EBNA1 model comparison.The EBV B95-8 EBNA1 sequence was input to I-TASSER, which selected the EBNA1 C-terminal domain crystal structure (1B3T) and several fragment templates comprising: yeast fatty acid synthetase (2PFF), a-L-fucosidase (2Z8X), photosynthetic reaction centre (1C51), type A collagen (1YOF) and dimeric 6-phosphoglucouronate dehydrogenase (2ZYD). The 1B3T template was also used to generate models in MOE. EBNA1 models constructed using I-TASSER and MOE (and the composite of these two generated in Modeller9v8 (shown above), were assessed for structural plausibility using Molprobity and QMEAN score servers (table S1). Models were superimposed over the template (1B3T) and RMSD was estimated for each. The qualitative model energy analysis, normalised (QMEANnorm) score of a protein structural model provides a composite scoring function based on several geometrical aspects, both global (for the entire structure) and local (per residue), enabling the discrimination of good and bad models. The human and other primate LCV EBNA1 protein structure models (as indicated) were ...

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Protein Interaction Domains of the Ubiquitin-specific Protease, USP7/HAUSP

Cited by 161 publications

References 39 publications

Epstein–Barr virus oncogenesis and the ubiquitin–proteasome system

Epstein–Barr virus oncogenesis and the ubiquitin–proteasome system

Epstein-Barr virus nuclear antigen 1 does not induce lymphoma in transgenic FVB mice

Modelling the structure of full-length Epstein–Barr virus nuclear antigen 1

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