Role of ATM in the Formation of the Replication Compartment during Lytic Replication of Epstein-Barr Virus in Nasopharyngeal Epithelial Cells

Hau, Pok Man; Deng, Wen; Jia, Lin; Yang, Jie; Tsurumi, Tatsuya; Chiang, Alan Kwok Shing; Huen, Michael S. Y.; Tsao, Sai Wah

doi:10.1128/jvi.01437-14

Cited by 44 publications

(49 citation statements)

References 68 publications

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“…However, the involvement of cellular pathways in mediating lytic induction seems to be varying in different cell types and upon treatment with different stimuli. For instance, although the ATM pathway was shown to be crucial for the regulation of EBV lytic cycle reactivation, other findings have also suggested that ATM was only involved in the stage of viral DNA replication rather than the initial step of lytic reactivation . Our data seem to support the latter argument because ATM inhibitor did not abrogate the lytic cycle reactivation by romidepsin in both NPC and GC cell lines in our study (refer to Fig.…”

Section: Discussionsupporting

confidence: 87%

Inhibition of class I histone deacetylases by romidepsin potently induces Epstein-Barr virus lytic cycle and mediates enhanced cell death with ganciclovir

et al. 2015

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Pan-histone deacetylase (HDAC) inhibitors, which inhibit 11 HDAC isoforms, are widely used to induce Epstein-Barr virus (EBV) lytic cycle in EBV-associated cancers in vitro and in clinical trials. Here, we hypothesized that inhibition of one or several specific HDAC isoforms by selective HDAC inhibitors could potently induce EBV lytic cycle in EBV-associated malignancies such as nasopharyngeal carcinoma (NPC) and gastric carcinoma (GC). We found that inhibition of class I HDACs, particularly HDAC-1, -2 and -3, was sufficient to induce EBV lytic cycle in NPC and GC cells in vitro and in vivo. Among a panel of selective HDAC inhibitors, the FDA-approved HDAC inhibitor romidepsin was found to be the most potent lytic inducer, which could activate EBV lytic cycle at~0.5 to 5 nM (versus~800 nM achievable concentration in patients' plasma) in more than 75% of cells. Upregulation of p21 WAF1 , which is negatively regulated by class I HDACs, was observed before the induction of EBV lytic cycle.The upregulation of p21 WAF1 and induction of lytic cycle were abrogated by a specific inhibitor of PKC-d but not the inhibitors of PI3K, MEK, p38 MAPK, JNK or ATM pathways. Interestingly, inhibition of HDAC-1, 22 and 23 by romidepsin or shRNA knockdown could confer susceptibility of EBV-positive epithelial cells to the treatment with ganciclovir (GCV). In conclusion, we demonstrated that inhibition of class I HDACs by romidepsin could potently induce EBV lytic cycle and mediate enhanced cell death with GCV, suggesting potential application of romidepsin for the treatment of EBV-associated cancers.

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Section: Discussionsupporting

confidence: 87%

Inhibition of class I histone deacetylases by romidepsin potently induces Epstein-Barr virus lytic cycle and mediates enhanced cell death with ganciclovir

et al. 2015

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“…Conceivably, lytic viral proteins, such as BZLF1 or BGLF4, may promote the late activation of ATM to enhance EBV replication through induction of cell cycle arrest and the assembly of replication compartments that are regulated by the kinase. 38 In line with the notion that SP1 regulates the BZLF1 promoter, we found that the effects of TPA/Bu and DNA damage converge on activation of this cellular transcription factor. SP1 may serve both as transcriptional repressor and activator depending on the recruitment of HDAC-containing repressor complexes.…”

Section: Discussionsupporting

confidence: 85%

“…Indeed, the phosphorylation of ATM and H2AX observed in cells exposed to TPA/Bu for 24 hr was not associated with activation of a canonical DDR, as assessed by failure to detect ubiquitination of H2AX, phosphorylation of KAP1 and p53, and expression of p21. Conceivably, lytic viral proteins, such as BZLF1 or BGLF4, may promote the late activation of ATM to enhance EBV replication through induction of cell cycle arrest and the assembly of replication compartments that are regulated by the kinase . In line with the notion that SP1 regulates the BZLF1 promoter, we found that the effects of TPA/Bu and DNA damage converge on activation of this cellular transcription factor.…”

Section: Discussionsupporting

confidence: 79%

A bacterial genotoxin causes virus reactivation and genomic instability in Epstein–Barr virus infected epithelial cells pointing to a role of co‐infection in viral oncogenesis

Frisan

Nagy

Chioureas

et al. 2018

Intl Journal of Cancer

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We have addressed the role of bacterial co-infection in viral oncogenesis using as model Epstein-Barr virus (EBV), a human herpesvirus that causes lymphoid malignancies and epithelial cancers. Infection of EBV carrying epithelial cells with the common oral pathogenic Gram-negative bacterium Aggregatibacter actinomycetemcomitans (Aa) triggered reactivation of the productive virus cycle. Using isogenic Aa strains that differ in the production of the cytolethal distending toxin (CDT) and purified catalytically active or inactive toxin, we found that the CDT acts via induction of DNA double strand breaks and activation of the Ataxia Telangectasia Mutated (ATM) kinase. Exposure of EBV-negative epithelial cells to the virus in the presence of sub-lethal doses of CDT was accompanied by the accumulation of latently infected cells exhibiting multiple signs of genomic instability. These findings illustrate a scenario where co-infection with certain bacterial species may favor the establishment of a microenvironment conducive to the EBV-induced malignant transformation of epithelial cells.

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“…In vitro EBV re-infection in nasopharyngeal epithelial cells has been able to suppress endogenous ATM expression and, sequentially, ATM kinase activity followed by exposure to IR [23]. The indispensable role of ATM in viral replication was also demonstrated in our recent study [24]. However, the involvement of EBV in ATM regulation has remained elusive and needs further investigation.…”

Section: Introductionmentioning

confidence: 51%

“…We have previously demonstrated that the ATM protein is consistently downregulated in EBV‐positive NPC and contributes to viral replication during EBV lytic reactivation in epithelial cells . Based on these findings, we hypothesize that the highly expressed miR‐BARTs are responsible for ATM regulation and subsequently inhibiting EBV lytic reactivation in NPC cells.…”

Section: Resultsmentioning

confidence: 82%

EBV‐encoded miRNAs target ATM‐mediated response in nasopharyngeal carcinoma

Lung

Hau

et al. 2018

The Journal of Pathology

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Nasopharyngeal carcinoma (NPC) is a highly invasive epithelial malignancy that is prevalent in southern China and Southeast Asia. It is consistently associated with latent Epstein–Barr virus (EBV) infection. In NPC, miR‐BARTs, the EBV‐encoded miRNAs derived from BamH1‐A rightward transcripts, are abundantly expressed and contribute to cancer development by targeting various cellular and viral genes. In this study, we establish a comprehensive transcriptional profile of EBV‐encoded miRNAs in a panel of NPC patient‐derived xenografts and an EBV‐positive NPC cell line by small RNA sequencing. Among the 40 miR‐BARTs, predominant expression of 22 miRNAs was consistently detected in these tumors. Among the abundantly expressed EBV‐miRNAs, BART5‐5p, BART7‐3p, BART9‐3p, and BART14‐3p could negatively regulate the expression of a key DNA double‐strand break (DSB) repair gene, ataxia telangiectasia mutated (ATM), by binding to multiple sites on its 3'‐UTR. Notably, the expression of these four miR‐BARTs represented more than 10% of all EBV‐encoded miRNAs in tumor cells, while downregulation of ATM expression was commonly detected in all of our tested sequenced samples. In addition, downregulation of ATM was also observed in primary NPC tissues in both qRT‐PCR (16 NP and 45 NPC cases) and immunohistochemical staining (35 NP and 46 NPC cases) analysis. Modulation of ATM expression by BART5‐5p, BART7‐3p, BART9‐3p, and BART14‐3p was demonstrated in the transient transfection assays. These findings suggest that EBV uses miRNA machinery as a key mechanism to control the ATM signaling pathway in NPC cells. By suppressing these endogenous miR‐BARTs in EBV‐positive NPC cells, we further demonstrated the novel function of miR‐BARTs in inhibiting Zta‐induced lytic reactivation. These findings imply that the four viral miRNAs work co‐operatively to modulate ATM activity in response to DNA damage and to maintain viral latency, contributing to the tumorigenesis of NPC. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Role of ATM in the Formation of the Replication Compartment during Lytic Replication of Epstein-Barr Virus in Nasopharyngeal Epithelial Cells

Cited by 44 publications

References 68 publications

Inhibition of class I histone deacetylases by romidepsin potently induces Epstein-Barr virus lytic cycle and mediates enhanced cell death with ganciclovir

Inhibition of class I histone deacetylases by romidepsin potently induces Epstein-Barr virus lytic cycle and mediates enhanced cell death with ganciclovir

A bacterial genotoxin causes virus reactivation and genomic instability in Epstein–Barr virus infected epithelial cells pointing to a role of co‐infection in viral oncogenesis

EBV‐encoded miRNAs target ATM‐mediated response in nasopharyngeal carcinoma

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