Epstein–Barr virus BZLF1 protein impairs accumulation of host DNA damage proteins at damage sites in response to DNA damage

Yang, Jie; Deng, Wen; Hau, Pok Man; Liu, Jia; Lau, V.K.N.; Cheung, Any; Huen, Michael S.Y.; Tsao, Sai Wah

doi:10.1038/labinvest.2015.69

Cited by 24 publications

(18 citation statements)

References 73 publications

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“…Phosphorylated H2AX, a mediator of DDR, was found to be associated with EBV infection in NPC cells 27 . In the present study, NPC cells exhibited γH2AX expression upon EBV infection, consistent with the results of a previous study 28 . Moreover, our findings demonstrate that EBV infection leads to activation of ATR; a similar effect of EBV was also detected in B lymphocytes 22 .…”

Section: Discussionsupporting

confidence: 93%

Epstein-Barr virus-induced up-regulation of TCAB1 is involved in the DNA damage response in nasopharyngeal carcinoma

Wang

Cui

et al. 2017

Sci Rep

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Telomerase Cajal body protein 1 (TCAB1), which is involved in Cajal body maintenance, telomere elongation and ribonucleoprotein biogenesis, has been linked to cancer predisposition, including nasopharyngeal carcinoma (NPC), due to its oncogenic properties. However, there are no specific reports to date on the functional relevance of TCAB1 and Epstein–Barr virus (EBV), which is considered to be a risk factor for NPC. In this study, we first examined NPC clinical tissues and found a notable overexpression of TCAB1 in EBV-positive specimens. Secondly, on a cellular level, we also observed that TCAB1 expression rose gradually along with the increased duration of EBV exposure in NPC cell lines. Additionally, EBV infection promoted cell proliferation and telomerase activity, but the activation was significantly inhibited after TCAB1 knockdown. Moreover, depletion of TCAB1 caused both cell cycle arrest and apoptosis, and suppressed the activation of ataxia telangiectasia and Rad3 related protein (ATR) induced by EBV, resulting in accumulation of DNA damage. Taken together, we here demonstrate that up-regulated expression of TCAB1, induced by EBV in the development of NPC, is involved in stimulating telomerase activity and regulating the DNA damage response within the context of EBV infection.

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Section: Discussionsupporting

confidence: 93%

Epstein-Barr virus-induced up-regulation of TCAB1 is involved in the DNA damage response in nasopharyngeal carcinoma

Wang

Cui

et al. 2017

Sci Rep

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“…It is therefore likely that BZLF1 indirectly targets ULBP2 gene transcription and/or that BZLF1 indirectly targets ULBP2 posttranscriptionally. It is known that BZLF1 binds to DNA damage response proteins, causing their mislocalization and, consequently, increased DNA damage in cells expressing BZLF1 (35). NKG2D ligands are known to be upregulated in response to a number of stress signals, including DNA damage (36), raising the possibility that upregulation of NKG2D ligands by BZLF1 may be an indirect result of induced DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Induction of the Lytic Cycle Sensitizes Epstein-Barr Virus-Infected B Cells to NK Cell Killing That Is Counteracted by Virus-Mediated NK Cell Evasion Mechanisms in the Late Lytic Cycle

Williams

Quinn

Rowe

et al. 2016

J Virol

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Epstein-Barr Virus (EBV) persists for the lifetime of the infected host despite eliciting strong immune responses. This persistence requires a fine balance between the host immune system and EBV immune evasion. Accumulating evidence suggests an important role for natural killer (NK) cells in this balance. NK cells can kill EBV-infected cells undergoing lytic replication in vitro, and studies in both humans and mice with reconstituted human immune systems have shown that NK cells can limit EBV replication and prevent infectious mononucleosis. We now show that NK cells, via NKG2D and DNAM-1 interactions, recognize and kill EBV-infected cells undergoing lytic replication and that expression of a single EBV lytic gene, BZLF1, is sufficient to trigger sensitization to NK cell killing. We also present evidence suggesting the possibility of the existence of an as-yet-unidentified DNAM-1 ligand which may be particularly important for killing lytically infected normal B cells. Furthermore, while cells entering the lytic cycle become sensitized to NK cell killing, we observed that cells in the late lytic cycle are highly resistant. We identified expression of the vBcl-2 protein, BHRF1, as one effective mechanism by which EBV mediates this protection. Thus, contrary to the view expressed in some reports, EBV has evolved the ability to evade NK cell responses. IMPORTANCEThis report extends our understanding of the interaction between EBV and host innate responses. It provides the first evidence that the susceptibility to NK cell lysis of EBV-infected B cells undergoing lytic replication is dependent upon the phase of the lytic cycle. Induction of the lytic cycle is associated with acquired sensitization to NK cell killing, while progress through the late lytic cycle is associated with acquired resistance to killing. We provide mechanistic explanations for this novel observation, indicating important roles for the BZLF1 immediate early transactivator, the BHRF1 vBcl-2 homologue, and a novel ligand for the DNAM-1 NK cell receptor. E pstein-Barr Virus (EBV), one of eight human herpesviruses, is carried by over 90% of the world's adult population. Primary EBV infection occurs in the oropharynx, leading to infection of B lymphocytes (1, 2). These infected B cells can support the lytic cycle, in which more than 80 viral genes are expressed to generate new infectious virus, but they more frequently host nonproductive infections through expression of a limited number of socalled latent EBV genes (latency III genes) that drive lymphoproliferation as an alternative mechanism of expanding the infected cell pool. In vitro, this growth transformation is demonstrated by the ready establishment of lymphoblastoid cell lines (LCLs) following infection of resting B cells. Following initial infection in vivo, EBV downregulates the expression of all viral proteins and enters a true latent phase (latency 0) in the memory B cell population, where it establishes a lifelong infection (1). Periodically the virus reactivates and undergoes fu...

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“…BZLF1 functions to bind with several DNA damage response (DDR) proteins and thus impair DNA damage repair and abrogate G2/M checkpoint, which induced genomic instability. In summary, BZLF1 contributes to the carcinogenesis of EBV-associated epithelial malignancies by induction of mis-localization of important DDR proteins, and BZLF1 may be the connection of lytic EBV infection with impaired DNA damage repair [55]. …”

Section: Other Moleculesmentioning

confidence: 99%

Role of Epstein-Barr virus in the development of nasopharyngeal carcinoma

Zhang

Wang

et al. 2017

Open Medicine

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AbstractSouthern China experiences larger extent of total cancer pathologies, of which nasopharyngeal carcinoma has the highest incidence under otorhinolaryngeal malignant carcinomas. Risk factor of nasopharyngeal carcinoma varies from hereditary causes to virus infection, among which Epstein-Barr virus (EBV) infection is the mostly investigated. The study into mechanism of EBV in occurrence, development and prognosis of nasopharyngeal carcinoma has been studied for several decades. The pathophysiology in making of EBV into a cancerogen includes proteins as latent membrane protein 1 (LMPs) and nucleic acids as micro-RNAs. In this paper, we reviewed till date studies focusing on relationship between EBV and nasopharyngeal carcinoma.

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Epstein–Barr virus BZLF1 protein impairs accumulation of host DNA damage proteins at damage sites in response to DNA damage

Cited by 24 publications

References 73 publications

Epstein-Barr virus-induced up-regulation of TCAB1 is involved in the DNA damage response in nasopharyngeal carcinoma

Epstein-Barr virus-induced up-regulation of TCAB1 is involved in the DNA damage response in nasopharyngeal carcinoma

Induction of the Lytic Cycle Sensitizes Epstein-Barr Virus-Infected B Cells to NK Cell Killing That Is Counteracted by Virus-Mediated NK Cell Evasion Mechanisms in the Late Lytic Cycle

Role of Epstein-Barr virus in the development of nasopharyngeal carcinoma

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