Epstein–Barr virus latent membrane protein 1 represses p53-mediated DNA repair and transcriptional activity

Liu, Ming‐Tsan; Chang, Yu-Ting; Chen, Shu‐Chuan; Chuang, Yu-Chia; Chen, Yiren; Lin, Chang-Shen; Chen, Jen‐Yang

doi:10.1038/sj.onc.1208319

Cited by 54 publications

(50 citation statements)

References 61 publications

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“…It has been observed that expression of EBV LMP1 protein represses p53-mediated DNA repair and transcriptional activity through the activation of the NF-B pathway. This suggests that the abrogation of DNA repair by LMP1 may induce genomic instability and contribute subsequently to tumorigenesis (37,38). Here we propose that EBV BKRF3 may function in addition to LMP1 to contribute to genome instability, thus favoring AID/UNG-induced c-myc/IgH translocations.…”

Section: Discussionmentioning

confidence: 93%

Characterization of the Uracil-DNA Glycosylase Activity of Epstein-Barr Virus BKRF3 and Its Role in Lytic Viral DNA Replication

Huang

Wang

et al. 2007

J Virol

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Uracil-DNA glycosylases (UDGs) of the uracil-N-glycosylase (UNG) family are the primary DNA repair enzymes responsible for removal of inappropriate uracil from DNA. Recent studies further suggest that the nuclear human UNG2 and the UDGs of large DNA viruses may coordinate with their DNA polymerase accessory factors to enhance DNA replication. Based on its amino acid sequence, the putative UDG of Epstein-Barr virus (EBV), BKRF3, belongs to the UNG family of proteins, and it was demonstrated previously to enhance oriLyt-dependent DNA replication in a cotransfection replication assay. However, the expression and enzyme activity of EBV BKRF3 have not yet been characterized. In this study, His-BKRF3 was expressed in bacteria and purified for biochemical analysis. Similar to the case for the Escherichia coli and human UNG enzymes, His-BKRF3 excised uracil from single-stranded DNA more efficiently than from double-stranded DNA and was inhibited by the purified bacteriophage PBS1 inhibitor Ugi. In addition, BKRF3 was able to complement an E. coli ung mutant in rifampin and nalidixic acid resistance mutator assays. The expression kinetics and subcellular localization of BKRF3 products were detected in EBV-positive lymphoid and epithelial cells by using BKRF3-specific mouse antibodies. Expression of BKRF3 is regulated mainly by the immediateearly transcription activator Rta. The efficiency of EBV lytic DNA replication was slightly affected by BKRF3 small interfering RNA (siRNA), whereas cellular UNG2 siRNA or inhibition of cellular and viral UNG activities by expressing Ugi repressed EBV lytic DNA replication. Taking these results together, we demonstrate the UNG activity of BKRF3 in vitro and in vivo and suggest that UNGs may participate in DNA replication or repair and thereby promote efficient production of viral DNA.

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Section: Discussionmentioning

confidence: 93%

Characterization of the Uracil-DNA Glycosylase Activity of Epstein-Barr Virus BKRF3 and Its Role in Lytic Viral DNA Replication

Huang

Wang

et al. 2007

J Virol

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“…Latent phase genes of EBV including Zta, LMP1, LMP2A, LMP2B. EBNA1, EBNA2, BGLF4, EBNA3C and truncated LMP1 genes (DX, DT, DBX, DS, D189-222, D189-321 and D350-389) were also sub-cloned into pSG5 expression vector (Liebowitz et al, 1992;Liu et al, 2005). The shRNAi sequences were shown as follows: 145-165, 5 0 -CTCCACTCCCTTCTCCAAAAG-3 0 and 1066-1086, 5 0 -CTGCCCAGTGTAGGTGTATTC-3 0 .…”

Section: Methodsmentioning

confidence: 99%

“…TW01 and HONE1 cells, human NPC cell lines, were maintained in Dulbecco's modified Eagle's medium supplemented with 10% fetal calf serum (Liu et al, 2005;Fang et al, 2009). …”

Section: Methodsmentioning

confidence: 99%

Functional interaction of Ugene and EBV infection mediates tumorigenic effects

et al. 2011

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Epstein-Barr virus (EBV) infection is associated with many human neoplasms, in which EBV-derived latent membrane protein-1 (LMP1) appears to be critical, but its exact oncogenic mechanism remains to be defined. To this end, our initial microarray analyses identified a LMP1-inducible gene, Ugene, originally characterized as a binding partner for uracil DNA glycosylase 2, which is highly expressed in malignant colon cancer. In this report, it was found that Ugene, designated herein as LMP1-induced protein (LMPIP), was induced, in a time-dependent manner, in EBV-infected peripheral blood mononuclear cells and LMP1-transfected 293 cells. Functionally, when compared with mock-transfected cells, overexpression of LMPIP in nasopharyngeal carcinoma (NPC) cell lines resulted in a decrease in reactive oxygen species production and maintained mitochondria membrane potential (Dw) loss induced by H 2 O 2 . The NPC cells transfected with LMPIP also showed a decrease in G1 population and an increase in the cell population in sub-G1 and multiploid phase, concomitant with increased levels of cell cycle activators, including cyclin D1 and CDK4. In contrast, silencing of LMPIP expression in the NPC tumor cell lines with short hairpin RNA interference revealed significantly decreased cell population at G1/S phase, while the number of cells in multiploid phase increased. Significantly, NPC cells with LMPIP knock-down also showed a decrease in tumorigenic and transforming activity induced by ectopic LMP1 expression, as determined by analyses of soft agar foci and tumor size in nude mice. Further, elevated LMPIP expression was also noted in cytoplasm and nuclei in EBVinfected NPC tumor cell mass and non-EBV-infected tumor cell lines. These results suggested that LMPIP may have an important mediator role in EBV-mediated neoplasm and may serve as a new target for therapy of tumors induced by EBV infection.

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“…Data in cell culture indicate that LMP1 upregulates A20, which can block p53-mediated apoptosis (Laherty et al, 1992;Fries et al, 1996). Furthermore, LMP1 represses p53-mediated DNA repair and transcriptional activity and this activity is dependent on the NF-kB pathway (Liu et al, 2005). The presence of elevated p53 protein and lack of mutations in LMP1-positive mouse lymphomas suggests that LMP1 also affects p53 expression and function in vivo.…”

Section: Signaling and Activation Of Nf-jb In Lmp1 Transgenic Mice Njmentioning

confidence: 99%

LMP1 signaling and activation of NF-κB in LMP1 transgenic mice

et al. 2005

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Transgenic mice expressing Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) under the control of an immunoglobulin heavy-chain promoter and enhancer develop lymphoma at a threefold higher incidence than LMP1-negative mice. In vitro, LMP1 activates numerous signaling pathways including p38, c-Jun N terminal kinase (JNK), phosphatidylinositol 3 kinase (PI3K)/Akt, and NF-jB through interactions with tumor necrosis receptorassociated factors (TRAFs). These pathways are frequently activated in EBV-associated malignancies, although their activation cannot be definitively linked to LMP1 expression in vivo. In this study, interactions between LMP1 and TRAFs and the activation of PI3K/ Akt, JNK, p38, and NF-jB were examined in LMP1 transgenic mice. LMP1 co-immunoprecipitated with TRAFs 1, 2, and 3. Akt, JNK, and p38 were activated in LMP1-positive and -negative splenocytes as well as LMP1-positive and -negative lymphomas. Multiple forms of NF-jB were activated in healthy splenocytes from LMP1 transgenic mice, in contrast to healthy splenocytes from LMP1-negative mice. However, in both LMP1-positive and -negative lymphomas, only the oncogenic NF-jB c-Rel, was specifically activated. Similarly to EBV-associated malignancies, p53 protein was detected at high levels in the transgenic lymphomas, although mutations were not detected in the p53 gene. These data indicate that NF-jB is activated in LMP1-positive healthy splenocytes; however, NF-jB c-Rel is specifically activated in both the transgenic lymphomas and in the rare lymphomas that develop in negative mice. The LMP1-mediated activation of NF-jB may contribute to the specific activation of c-Rel and lead to the increased development of lymphoma in the LMP1 transgenic mice.

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Epstein–Barr virus latent membrane protein 1 represses p53-mediated DNA repair and transcriptional activity

Cited by 54 publications

References 61 publications

Characterization of the Uracil-DNA Glycosylase Activity of Epstein-Barr Virus BKRF3 and Its Role in Lytic Viral DNA Replication

Characterization of the Uracil-DNA Glycosylase Activity of Epstein-Barr Virus BKRF3 and Its Role in Lytic Viral DNA Replication

Functional interaction of Ugene and EBV infection mediates tumorigenic effects

LMP1 signaling and activation of NF-κB in LMP1 transgenic mice

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