Functional advantage of NPC-related V-val subtype of Epstein-Barr virus nuclear antigen 1 compared with prototype in epithelial cell line

Shi, Juan; Ooka, Tadamasa; Li, Da Jiang; Zeng, Mu Sheng; Jiang, Ri Cheng; Yu, Xinmiao; Zhang, Ru Hua; Chen, Shi Ping; Zeng, Yi Xin

doi:10.3892/or.17.1.141

Cited by 16 publications

(18 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is known that NPC, EBVaGC and nasal NK/T-cell lymphoma are more prevalent in Asia than in other part of the world [44], thus, it is likely that V-val subtype might be more aggressive than other subtypes. Recently, Mai et al [45] and Do et al [46] demonstated that V-val subtype had functional advantage and higher transcriptional activity than P-ala subtype (the B95.8 prototype). As compared with the prototype P-ala, V-val subtype showed 7 amino acid substitutions (codons 439, 487, 499, 502, 524, 528 and 533) with respect to the carboxyl-terminus of EBNA1.…”

Section: Discussionmentioning

confidence: 99%

Variations of Epstein-Barr Virus Nuclear Antigen 1 in Epstein-Barr Virus-Associated Gastric Carcinomas from Guangzhou, Southern China

et al. 2012

View full text Add to dashboard Cite

Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) is the only viral protein consistently expressed in all EBV-associated malignancies, and play a critical role in the onset, progression, and/or maintenance of these tumors. Based on the signature changes at amino acid residue 487, EBNA1 is classified into five distinct subtypes: P-ala, P-thr, V-leu, V-val and V-pro. In the present study, the sequence variations of EBNA1 in EBV-associated gastric carcinoma (EBVaGC) and throat washing (TW) samples of healthy EBV carriers in Guangzhou, southern China, where nasopharyngeal carcinoma (NPC) is endemic, were analyzed by PCR and DNA sequencing. V-val subtype was the most predominant (53.6%, 15/28) in EBVaGC, followed by P-ala (42.9%, 12/28) and V-leu (32.1%, 9/28) subtypes. In TWs of healthy EBV carriers, V-val subtype was also predominant (85.7%, 18/21). The sequence variations of EBNA1 in EBVaGC were similar to those in TW of healthy EBV carriers (p>0.05), suggesting that the EBV strains in EBVaGC might originate from the viral strains prevalent within the background population. The predominance of V-val subtype in EBVaGC in Guangzhou was similar to that in EBVaGC in northern China and Japan, but was different from that in EBVaGC in America, suggesting that the variations of EBNA1 in EBVaGC represent geographic-associated polymorphisms rather than tumor-specific mutations. In addition, the EBNA1 variations in EBVaGC in gastric remnant carcinoma were also determined. V-leu subtype was detected in all 4 (100%) cases, although 2 cases occurred as mixed infection with P-ala subtype. This is different from the predominant V-val subtype in EBVaGC in conventional gastric carcinoma, suggesting that V-leu might be a subtype that adapts particularly well to the microenvironment within the gastric stump and enters the remnant gastric mucosa epithelia easily. This, to our best knowledge, is the first investigation of EBNA1 polymorphisms in EBVaGC from endemic area of NPC.

show abstract

Section: Discussionmentioning

confidence: 99%

Variations of Epstein-Barr Virus Nuclear Antigen 1 in Epstein-Barr Virus-Associated Gastric Carcinomas from Guangzhou, Southern China

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Genetic analyses of various EBV strains indicate that T585 is among the EBNA1 polymorphisms found frequently in both NPC tumors and Burkitt's lymphoma (35)(36)(37)(38)(39)(40)(41). Recently, our laboratory found that an NPC variant of EBNA1 containing 8 amino acid polymorphisms different from the prototypical B95-8 strain, including a T585I substitution, was defective in replication and maintenance of the viral episome (41).…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Basis for an EBNA1 Hexameric Ring in Epstein-Barr Virus Episome Maintenance

Deakyne

Malecka

Messick

et al. 2017

J Virol

View full text Add to dashboard Cite

Epstein-Barr virus (EBV) establishes a stable latent infection that can persist for the life of the host. EBNA1 is required for the replication, maintenance, and segregation of the latent episome, but the structural features of EBNA1 that confer each of these functions are not completely understood. Here, we have solved the X-ray crystal structure of an EBNA1 DNA-binding domain (DBD) and discovered a novel hexameric ring oligomeric form. The oligomeric interface pivoted around residue T585 as a joint that links and stabilizes higher-order EBNA1 complexes. Substitution mutations around the interface destabilized higher-order complex formation and altered the cooperative DNA-binding properties of EBNA1. Mutations had both positive and negative effects on EBNA1-dependent DNA replication and episome maintenance with OriP. We found that one naturally occurring polymorphism in the oligomer interface (T585P) had greater cooperative DNA binding in vitro, minor defects in DNA replication, and pronounced defects in episome maintenance. The T585P mutant was compromised for binding to OriP in vivo as well as for assembling the origin recognition complex subunit 2 (ORC2) and trimethylated histone 3 lysine 4 (H3K4me3) at OriP. The T585P mutant was also compromised for forming stable subnuclear foci in living cells. These findings reveal a novel oligomeric structure of EBNA1 with an interface subject to naturally occurring polymorphisms that modulate EBNA1 functional properties. We propose that EBNA1 dimers can assemble into higher-order oligomeric structures important for diverse functions of EBNA1.IMPORTANCE Epstein-Barr virus is a human gammaherpesvirus that is causally associated with various cancers. Carcinogenic properties are linked to the ability of the virus to persist in the latent form for the lifetime of the host. EBNA1 is a sequencespecific DNA-binding protein that is consistently expressed in EBV tumors and is the only viral protein required to maintain the viral episome during latency. The structural and biochemical mechanisms by which EBNA1 allows the long-term persistence of the EBV genome are currently unclear. Here, we have solved the crystal structure of an EBNA1 hexameric ring and characterized key residues in the interface required for higher-order complex formation and long-term plasmid maintenance.KEYWORDS DNA-binding domain, EBNA1, Epstein-Barr virus, OriP, cooperative binding, hexameric ring, oligomers, episome maintenance, viral latency E pstein-Barr virus (EBV) is a ubiquitous human herpesvirus that establishes long-term latent infection in more than 90% of the human population (1-6). Latent infection by EBV is estimated to be responsible for over 200,000 cancers worldwide, including subtypes of Burkitt's lymphoma, diffuse large B-cell lymphoma, primary central nervous system lymphoma, and Hodgkin's lymphoma as well as gastric carcinoma and nasopharyngeal carcinoma (NPC) (1-4). Epstein-Barr virus nuclear antigen 1 (EBNA1) is the only viral protein consistently expressed in all EBV-associate...

show abstract

“…The exact role of EBV in the pathogenesis of EBV-associated malignancies remains to be determined. The fact that EBV infection is ubiquitous around the world yet the incidence of EBV-associated malignancies differs geographically raises the possibility that certain EBV strains may contribute to the development of specific EBV-associated malignancies [7,8,9,10,11]. …”

Section: Introductionmentioning

confidence: 99%

Epstein-Barr Virus EBNA-2 Polymorphic Patterns in Nasopharyngeal Carcinoma in Southern China

Liu

et al. 2015

Intervirology

View full text Add to dashboard Cite

Objectives: The aim of this study was to characterize the specific Epstein-Barr virus (EBV) polymorphisms from nasopharyngeal carcinoma (NPC) patients and healthy donors in Southern China, and to explore the relationship between EBV genotypes and NPC. Methods: The EBNA-2 gene of 32 EBV-positive NPCs and 39 EBV-positive throat washing (TW) samples from healthy individuals from Southern China was analyzed using PCR and sequencing. Results: We found E2-A to be the predominant subtype in Southern China. The distribution of EBNA-2 subtypes between NPCs and TWs was significantly different (p < 0.01) and the E2-A subtype was overly represented in NPCs. Conclusions: E2-A is the predominant subtype in Southern China, and the distribution of EBNA-2 subtypes between NPCs and TWs is significantly different. In Southern China, the E2-A subtype is significantly more frequent in NPCs than TWs, and is also more common than in Northern China. This suggests that the E2-A subtype may play an important role in the pathogenesis of NPC and that EBNA-2 gene variations are tumor-specific polymorphisms.

show abstract

Functional advantage of NPC-related V-val subtype of Epstein-Barr virus nuclear antigen 1 compared with prototype in epithelial cell line

Cited by 16 publications

References 23 publications

Variations of Epstein-Barr Virus Nuclear Antigen 1 in Epstein-Barr Virus-Associated Gastric Carcinomas from Guangzhou, Southern China

Variations of Epstein-Barr Virus Nuclear Antigen 1 in Epstein-Barr Virus-Associated Gastric Carcinomas from Guangzhou, Southern China

Structural and Functional Basis for an EBNA1 Hexameric Ring in Epstein-Barr Virus Episome Maintenance

Epstein-Barr Virus EBNA-2 Polymorphic Patterns in Nasopharyngeal Carcinoma in Southern China

Contact Info

Product

Resources

About