Enhancement of Zta-activated lytic transcription of Epstein-Barr virus by Ku80

Chen, Chien‐Chang; Yang, Ya-Chun; Wang, Wen Hung; Chen, Chien-Sin; Chang, Li-Kwan

doi:10.1099/vir.0.026302-0

Cited by 5 publications

(6 citation statements)

References 60 publications

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“…This positive feedback loop appears to be required for full promoter activation of BZLF1 . In addition, BZLF1 reportedly interacts with co‐activators, such as CREB‐binding protein , Ku80 and transducer of regulated CREB , to enhance activation of BZLF1‐dependent promoters.…”

Section: Transcription Factors That Mediate Bzlf1 Inductionmentioning

confidence: 98%

Regulation of Epstein–Barr virus reactivation from latency

Murata

2014

Microbiology and Immunology

112

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The Epstein-Barr virus (EBV) is a human gamma-herpesvirus that is implicated in various types of proliferative diseases. Upon infection, it predominantly establishes latency in B cells and cannot ever be eradicated; it persists for the host's lifetime. Reactivation of the virus from latency depends on expression of the viral immediate-early gene, BamHI Z fragment leftward open reading frame 1 (BZLF1). The BZLF1 promoter normally exhibits only low basal activity but is activated in response to chemical or biological inducers, such as 12-O-tetradecanoylphorbol-13-acetate, calcium ionophore, histone deacetylase inhibitor, or anti-Ig. Transcription from the BZLF1 promoter is activated by myocyte enhancer factor 2, specificity protein 1, b-Zip type transcription factors and mediating epigenetic modifications of the promoter, such as histone acetylation and H3K4me3. In contrast, repression of the promoter is mediated by transcriptional suppressors, such as ZEB, ZIIR-BP, and jun dimerization protein 2, causing suppressive histone modifications like histone H3K27me3, H3K9me2/3 and H4K20me3. Interestingly, there is little CpG DNA methylation of the promoter, indicating that DNA methylation is not crucial for suppression of BZLF1. This review will focus on the molecular mechanisms by which the EBV lytic switch is controlled and discuss the physiological significance of this switching for its survival and oncogenesis.

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Section: Transcription Factors That Mediate Bzlf1 Inductionmentioning

confidence: 98%

Regulation of Epstein–Barr virus reactivation from latency

Murata

2014

Microbiology and Immunology

112

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“…BZLF1 has been reported to bind to Ku80 through its C-terminal region. 23 This interaction may also prevent the Ku70/Ku80 proteins from binding to DNA DSB ends to serve as a scaffold for subsequent NHEJ repair reactions. Further work will be required to dissect the potential relationships among 53BP1, Ku80 and BZLF1 during NHEJ-mediated repair.…”

Section: Discussionmentioning

confidence: 99%

“…The DNA damage repair protein, Ku80, physically interacts with BZLF1. 23 The BZLF1 also binds to and activates p53 (refs. 24 and 25) in certain cell types, which suggests that BZLF1 has a role in inducing DNA damage.…”

mentioning

confidence: 99%

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

Yang

Deng

Hau

et al. 2015

Laboratory Investigation

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Epstein-Barr virus (EBV) infection is closely associated with several human malignancies including nasopharyngeal carcinoma (NPC). The EBV immediate-early protein BZLF1 is the key mediator that switches EBV infection from latent to lytic forms. The lytic form of EBV infection has been implicated in human carcinogenesis but its molecular mechanisms remain unclear. BZLF1 has been shown to be a binding partner of several DNA damage response (DDR) proteins. Its functions in host DDR remain unknown. Thus, we explore the effects of BZLF1 on cellular response to DNA damage in NPC cells. We found that expression of BZLF1 impaired the binding between RNF8 and MDC1 (mediator of DNA damage checkpoint 1), which in turn interfered with the localization of RNF8 and 53BP1 to the DNA damage sites. The RNF8-53BP1 pathway is important for repair of DNA double-strand breaks and DNA damage-induced G2/M checkpoint activation. Our results showed that, by impairing DNA damage repair as well as abrogating G2/M checkpoint, BZLF1 induced genomic instability and rendered cells more sensitive to ionizing radiation. Moreover, the blockage of 53BP1 and RNF8 foci formation was recapitulated in EBV-infected cells. Taken together, our study raises the possibility that, by causing mis-localization of important DDR proteins, BZLF1 may function as a link between lytic EBV infection and impaired DNA damage repair, thus contributing to the carcinogenesis of EBV-associated human epithelial malignancies. Epstein-Barr virus (EBV) is a gamma herpesvirus and infection with EBV is associated with a variety of epithelial and B-cell cancers. 1,2 EBV has a biphasic life cycle consisting of latent and lytic stages. The switch from latent to lytic infection is triggered by the EBV immediate-early transcription factor, BZLF1 (ZEBRA, Zta, Z, EB1). 3,4 A number of reports have demonstrated that lytic EBV activation is intimately linked to the pathogenesis of EBV-induced malignancies including the development of NPC. [5][6][7][8] The mammalian DNA damage response (DDR) network has pivotal roles in maintaining genome stability and tumor suppression. [9][10][11][12][13] In the presence of double-strand break (DSBs), the protein complex composed of MRE11-RAD50-NBS1 (MRN) recruits and activates the ataxia-telangiectasiamutated (ATM) kinase at the vicinity of DSBs, 10 which leads to the phosphorylation of the histone variant H2AX (γH2AX). γH2AX decorates chromatin domains flanking DSBs, and is directly engaged by the mediator of DNA damage checkpoint 1 (MDC1). MDC1 loading onto the damaged chromatin subsequently permits the productive accumulation of a cohort of DNA damage signaling and mediator proteins. 14,15 In particular, the RING finger ubiquitin ligase RNF8 is targeted to MDC1 via its phospho-binding forkheadassociated domain, where it initiates a cascade of chromatin ubiquitination events important for tethering of DNA damage mediator and repair proteins, including 53BP1 and BRCA1, [16][17][18][19] the dysregulation of which compromises genome stability and cont...

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“…In the lytic stage, EBV is known to induce DNA damage and to inhibit DNA repair leading to instability of the host genome [22,23]. One EBV component that has been associated with inhibition of NHEJ function in DSB repair is the transcription factor Zta, which is encoded by the BZLF1 gene and is crucial for lytic development of EBV [24]. Co-immunoprecipitation experiments have shown that the interaction of Ku80 with Zta can be mapped to the region associated with DNA binding and dimerization, between amino acids 168 and 245 of Zta.…”

Section: Epstein Barr Virusmentioning

confidence: 99%

Viral interactions with non-homologous end-joining: a game of hide-and-seek

Hristova

Lauer

Ferguson

2020

Journal of General Virology

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There are extensive interactions between viruses and the host DNA damage response (DDR) machinery. The outcome of these interactions includes not only direct effects on viral nucleic acids and genome replication, but also the activation of host stress response signalling pathways that can have further, indirect effects on viral life cycles. The non-homologous end-joining (NHEJ) pathway is responsible for the rapid and imprecise repair of DNA double-stranded breaks in the nucleus that would otherwise be highly toxic. Whilst directly repairing DNA, components of the NHEJ machinery, in particular the DNA-dependent protein kinase (DNA-PK), can activate a raft of downstream signalling events that activate antiviral, cell cycle checkpoint and apoptosis pathways. This combination of possible outcomes results in NHEJ being pro- or antiviral depending on the infection. In this review we will describe the broad range of interactions between NHEJ components and viruses and their consequences for both host and pathogen.

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Enhancement of Zta-activated lytic transcription of Epstein-Barr virus by Ku80

Cited by 5 publications

References 60 publications

Regulation of Epstein–Barr virus reactivation from latency

Regulation of Epstein–Barr virus reactivation from latency

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

Viral interactions with non-homologous end-joining: a game of hide-and-seek

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