Cellular transcription factors recruit viral replication proteins to activate the Epstein-Barr virus origin of lytic DNA replication, oriLyt

Baumann, Matthias; Feederle, Regina; Kremmer, Elisabeth; Hammerschmidt, Wolfgang

doi:10.1093/emboj/18.21.6095

Cited by 56 publications

(29 citation statements)

References 62 publications

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“…Sp1 is a major signaling pathway downstream of ATM. Its involvement in lytic replication of EBV in infected B cells had been reported in earlier studies (17,45). The involvement of Sp1 in the ATM-mediated lytic reactivation of EBV infection in epithelial cells has not been investigated.…”

Section: Lytic Reactivation Of Ebv-infected Cells Elicits a Dna Damagsupporting

confidence: 62%

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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

Hau

Deng

Jia

et al. 2015

J Virol

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Epstein-Barr virus (EBV), a type of oncogenic herpesvirus, is associated with human malignancies. Previous studies have shown that lytic reactivation of EBV in latently infected cells induces an ATM-dependent DNA damage response (DDR).The involvement of ATM activation has been implicated in inducing viral lytic gene transcription to promote lytic reactivation. Its contribution to the formation of a replication compartment during lytic reactivation of EBV remains poorly defined. In this study, the role of ATM in viral DNA replication was investigated in EBV-infected nasopharyngeal epithelial cells. We observed that induction of lytic infection of EBV triggers ATM activation and localization of DDR proteins at the viral replication compartments. Suppression of ATM activity using a small interfering RNA (siRNA) approach or a specific chemical inhibitor profoundly suppressed replication of EBV DNA and production of infectious virions in EBV-infected cells induced to undergo lytic reactivation. We further showed that phosphorylation of Sp1 at the serine-101 residue is essential in promoting the accretion of EBV replication proteins at the replication compartment, which is crucial for replication of viral DNA. Knockdown of Sp1 expression by siRNA effectively suppressed the replication of viral DNA and localization of EBV replication proteins to the replication compartments. Our study supports an important role of ATM activation in lytic reactivation of EBV in epithelial cells, and phosphorylation of Sp1 is an essential process downstream of ATM activation involved in the formation of viral replication compartments. Our study revealed an essential role of the ATM-dependent DDR pathway in lytic reactivation of EBV, suggesting a potential antiviral replication strategy using specific DDR inhibitors. IMPORTANCEEpstein-Barr virus (EBV) is closely associated with human malignancies, including undifferentiated nasopharyngeal carcinoma (NPC), which has a high prevalence in southern China. EBV can establish either latent or lytic infection depending on the cellular context of infected host cells. Recent studies have highlighted the importance of the DNA damage response (DDR), a surveillance mechanism that evolves to maintain genome integrity, in regulating lytic EBV replication. However, the underlying molecular events are largely undefined. ATM is consistently activated in EBV-infected epithelial cells when they are induced to undergo lytic reactivation. Suppression of ATM inhibits replication of viral DNA. Furthermore, we observed that phosphorylation of Sp1 at the serine-101 residue, a downstream event of ATM activation, plays an essential role in the formation of viral replication compartments for replication of virus DNA. Our study provides new insights into the mechanism through which EBV utilizes the host cell machinery to promote replication of viral DNA upon lytic reactivation.H erpesviruses belong to a large family of DNA viruses that can switch between latent and lytic cycles in infected host cells. They ar...

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Section: Lytic Reactivation Of Ebv-infected Cells Elicits a Dna Damagsupporting

confidence: 62%

“…Zta binds to the oriLyt and acts as a platform to tether other viral replication proteins (7,10,15,16). In addition, cellular factors are also recruited to the oriLyt, forming a scaffolding complex essential for the replication of viral DNA (17).…”

mentioning

confidence: 99%

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

Hau

Deng

Jia

et al. 2015

J Virol

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“…The BMRF1 and BZLF1 proteins co-localize within intranuclear viral replication compartments (50). The possibility has been pointed out that the direct interaction between BMRF1 and BZLF1 proteins modulates viral replication (21,25). In the present study, because deletion mutants BMRF1 ⌬1-10 and ⌬1-30 lacking the ability to bind to the BZLF1 protein did not enhance BZLF1-mediated transactivation of the BALF2 promoter (Fig.…”

Section: Discussionmentioning

confidence: 42%

“…therefore suggested that BMRF1 might enhance the transcriptional effects of ZBP-89 and SP1 bound to GC-rich motifs (22,24) because it interacts directly with these host transcription factors (22,24,25). Although the protein by itself had no stimulatory effect on the BALF2 promoter, we found two putative SP1-binding sites but no ZBP-89-binding site within the BALF2 promoter region by computer analysis (Fig.…”

Section: Discussionmentioning

confidence: 69%

“…Recently it has been shown to transcriptionally activate the EBV BHLF1 promoter, one of two divergent early promoters located within the lytic origin of viral DNA replication, oriLyt (21)(22)(23), as well as transactivating a cellular gastrin promoter (24). Interaction between BMRF1 protein and promoter-bound cellular transcriptional factors, such as ZBP-89 and/or SP1, appears to be essential for formation of initial transcriptional replication complexes to enhance transcription (24,25).…”

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confidence: 99%

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Epstein-Barr Virus Polymerase Processivity Factor Enhances BALF2 Promoter Transcription as a Coactivator for the BZLF1 Immediate-Early Protein

Nakayama

Murata

Murayama

et al. 2009

Journal of Biological Chemistry

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The Epstein-Barr virus (EBV) BMRF1 protein is an essential replication protein acting at viral replication forks as a viral DNA polymerase processivity factor, whereas the BALF2 protein is a singlestranded DNA-binding protein that also acts at replication forks and is most abundantly expressed during viral productive replication. Here we document that the BMRF1 protein evidently enhances viral BZLF1 transcription factor-mediated transactivation of the BALF2 gene promoter. Mutagenesis and electrophoretic mobility shift assays demonstrated the BALF2 promoter to harbor two BZLF1 protein-binding sites (BZLF1-responsive elements). Direct binding of the BZLF1 protein to BZLF1-responsive elements and physical interaction between BZLF1 and BMRF1 proteins are prerequisite for the BMRF1 protein up-regulation of the BALF2 gene promoter. A monomeric mutant, C95E, which is defective in homodimerization, could still interact and enhance BZLF1-mediated transactivation. Furthermore although EBV protein kinase phosphorylates BMRF1 protein extensively, it turned out that phosphorylation of the protein by the kinase is inhibitory to the enhancement of the BZLF1-mediated transactivation of BALF2 promoter. Exogenous expression of BMRF1 protein augmented BALF2 expression in HEK293 cells harboring the EBV genome but lacking BMRF1 and BALF5 genes, demonstrating functions as a transcriptional regulator in the context of viral infection. Overall the BMRF1 protein is a multifunctional protein that cannot only act as a DNA polymerase processivity factor but also enhances BALF2 promoter transcription as a coactivator for the BZLF1 protein, regulating the expression level of viral singlestranded DNA-binding protein.

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Latent and lytic Epstein‐Barr virus replication strategies

Tsurumi

Fujita

Kudoh

2004

Reviews in Medical Virology

210

199

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The Epstein-Barr virus (EBV) can choose between two alternative lifestyles; latent or lytic replication. In the latent state, the EBV genomic DNA, which exists as a closed circular plasmid, appears to behave just like host chromosomal DNA and it has been demonstrated recently that replication of OriP-containing plasmids is indeed dependent on the chromosomal initiation factors, ORC2 and Cdt1. On the other hand, in the viral productive cycle, the EBV genome is amplified 100- to 1000-fold by the viral replication machinery. EBV productive DNA replication occurs at discrete sites in nuclei, called replication compartments and the lytic programme arrests cell cycle progression and changes the cellular environment greatly. It has been revealed recently that the EBV lytic programme promotes an S-phase like cellular condition, which most favours viral lytic replication. This review describes recent advances regarding the molecular basis of EBV DNA replication during latent and lytic infections and then refers to cellular circumstances after induction of the lytic replication of EBV. Based on the molecular mechanism for the EBV lifestyle, purposeful induction of the lytic form of EBV infection is now advocated as one of the strategies for specific destruction of Epstein-Barr virus (EBV)-associated malignancies where the virus is latently infected.

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Cellular transcription factors recruit viral replication proteins to activate the Epstein-Barr virus origin of lytic DNA replication, oriLyt

Cited by 56 publications

References 62 publications

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

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

Epstein-Barr Virus Polymerase Processivity Factor Enhances BALF2 Promoter Transcription as a Coactivator for the BZLF1 Immediate-Early Protein

Latent and lytic Epstein‐Barr virus replication strategies

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