Structure of the p53 Binding Domain of HAUSP/USP7 Bound to Epstein-Barr Nuclear Antigen 1

Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
Molecular Cell (Impact Factor: 14.02). 05/2005; 18(1):25-36. DOI: 10.1016/j.molcel.2005.02.029
Source: PubMed


USP7/HAUSP is a key regulator of p53 and Mdm2 and is targeted by the Epstein-Barr nuclear antigen 1 (EBNA1) protein of Epstein-Barr virus (EBV). We have determined the crystal structure of the p53 binding domain of USP7 alone and bound to an EBNA1 peptide. This domain is an eight-stranded beta sandwich similar to the TRAF-C domains of TNF-receptor associated factors, although the mode of peptide binding differs significantly from previously observed TRAF-peptide interactions in the sequence (DPGEGPS) and the conformation of the bound peptide. NMR chemical shift analyses of USP7 bound by EBNA1 and p53 indicated that p53 binds the same pocket as EBNA1 but makes less extensive contacts with USP7. Functional studies indicated that EBNA1 binding to USP7 can protect cells from apoptotic challenge by lowering p53 levels. The data provide a structural and conceptual framework for understanding how EBNA1 might contribute to the survival of Epstein-Barr virus-infected cells.

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    • "Inactivation experiments in mice confirmed that regulation of p53 is a crucial, but not the only, function of USP7 (Kon et al., 2010, 2011). Targeting of USP7 by the viral EBNA1 protein or cellular TSPYL5 suppresses p53 function (Saridakis et al., 2005; Epping et al., 2011). USP7 activity may promote tumor suppression in breast cancer through the p53 pathway (Epping et al., 2011). "
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    ABSTRACT: Nucleotide biosynthesis is fundamental to normal cell proliferation as well as to oncogenesis. Tumor suppressor p53, which prevents aberrant cell proliferation, is destabilized through ubiquitylation by MDM2. Ubiquitin-specific protease 7 (USP7) plays a dualistic role in p53 regulation and has been proposed to deubiquitylate either p53 or MDM2. Here, we show that guanosine 5'-monophosphate synthase (GMPS) is required for USP7-mediated stabilization of p53. Normally, most GMPS is sequestered in the cytoplasm, separated from nuclear USP7 and p53. In response to genotoxic stress or nucleotide deprivation, GMPS becomes nuclear and facilitates p53 stabilization by promoting its transfer from MDM2 to a GMPS-USP7 deubiquitylation complex. Intriguingly, cytoplasmic sequestration of GMPS requires ubiquitylation by TRIM21, a ubiquitin ligase associated with autoimmune disease. These results implicate a classic nucleotide biosynthetic enzyme and a ubiquitin ligase, better known for its role in autoimmune disease, in p53 control.
    Molecular cell 01/2014; 53(3). DOI:10.1016/j.molcel.2013.12.017 · 14.02 Impact Factor
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    • "There are several mechanisms by which EBV could increase the risk of malignant transformation of infected cells. It was found that viral proteins inhibit apoptosis [16-18], affect the JAK/STAT pathway [19-22], promote epigenetic changes [23-25], and undermine the immune defense mechanisms [26] (see Table 1 for details). "
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    ABSTRACT: The etiology of childhood cancers has been studied for more than 40 years. However, most if not all cancers occurring in children are attributed to unknown causes. This review is focused on the role of infections in cancer development and progression in children. The main infectious agents include human herpesviruses, polyoma viruses, and human papilloma viruses. It is known that infections can lead to carcinogenesis through various mechanisms, and most likely act in addition to genetic and environmental factors. Given the importance of the infectious etiology of childhood cancers, clinical implications and possible prevention strategies are discussed.
    Infectious Agents and Cancer 12/2013; 8(1):48. DOI:10.1186/1750-9378-8-48 · 2.36 Impact Factor
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    • "In vivo EBNA1 has not been reported to lower Mdm2 levels, but has been confirmed to lower p53 levels at least in some cell backgrounds. For example, expression of EBNA1 but not a USP7-binding mutant of EBNA1 in U2OS cells was shown to reduce the accumulation of p53 in response to DNA damage and subsequent apoptosis [153]. Similarly, EBNA1 expression in CNE2 nasopharyngeal carcinoma (NPC) cells decreased the accumulation of p53 in response to DNA damage [156], and the presence of EBNA1 or EBV in AGS or SCM1 gastric carcinoma cells decreased the steady-state levels of p53 [135, 157]. "
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    ABSTRACT: Epstein-Barr virus (EBV) is a widespread human herpes virus that immortalizes cells as part of its latent infection and is a causative agent in the development of several types of lymphomas and carcinomas. Replication and stable persistence of the EBV genomes in latent infection require the viral EBNA1 protein, which binds specific DNA sequences in the viral DNA. While the roles of EBNA1 were initially thought to be limited to effects on the viral genomes, more recently EBNA1 has been found to have multiple effects on cellular proteins and pathways that may also be important for viral persistence. In addition, a role for EBNA1 in lytic infection has been recently identified. The multiple roles of EBNA1 in EBV infection are the subject of this paper.
    12/2012; 2012:438204. DOI:10.6064/2012/438204
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