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

Oncogene volume 24, pages 2635–2646 (2005)Cite this article

Abstract

The latent membrane protein 1 (LMP1) of Epstein–Barr virus (EBV), a viral oncogene, is essential for transformation of resting B cells by the virus. We previously demonstrated that LMP1 could repress DNA repair in p53-wild-type and p53-deficient human epithelial cells. In this study, using a host cell reactivation (HCR) assay, we demonstrated that p53-enhanced DNA repair was repressed by LMP1 in p53-deficient cells. Moreover, we found that LMP1 was able to repress p53-dependent transcriptional activity. Regarding the mechanisms of p53 repression by LMP1, we found that LMP1 did not inhibit p53 function through direct interaction, by promoting protein degradation or reducing its DNA-binding ability. Using chimeric proteins in the reporter assay, we demonstrated that LMP1 inhibited p53 transactivation by influencing the N-terminal transactivation domain of p53. Subsequent experiments using various LMP1 deletion mutants indicated that a C-terminus-activating region of LMP1, CTAR1 or CTAR2, is responsible for the repression of p53-mediated DNA repair and p53-dependent transcription, which is correlated with the region responsible for NF-κB activation. Furthermore, blockage of NF-κB signalling by IκB-ΔN was shown to abolish the repression of p53 by LMP1, suggesting that LMP1 likely repressed p53 function through the NF-κB pathway. Based on these results, we propose that inhibition of p53-dependent transcriptional activity and DNA repair by LMP1 results in the loss of p53 activity for maintaining genomic stability, which may contribute to the oncogenesis of LMP1 in human epithelial cells.

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Acknowledgements

We are indebted to Dr Tim J Harrison at Royal Free and University College Medical School, University College London for critical reading of the manuscript. This work was supported by grants from the National Science Council (Grants NSC 91-2320-B-002-100, NSC91-2320-B-002-178, NSC92-2320-B-002-162 and NSC92-2320-B-002-163) and National Health Research Institutes, Taiwan.

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  1. National Health Research Institutes, 3F No. 109, Section 6, Min-Chuan East Road, Taipei, 114, Taiwan

    Ming-Tsan Liu, Yu-Ting Chang, Shu-Chuan Chen, Chang-Shen Lin & Jen-Yang Chen

  2. Graduate Institute of Microbiology, College of Medicine, National Taiwan University, No. 1, Section 1, Jen-Ai Road, Taipei, 100, Taiwan

    Yu-Chia Chuang, Yi-Ren Chen & Jen-Yang Chen

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  1. Ming-Tsan Liu
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Liu, MT., Chang, YT., Chen, SC. et al. Epstein–Barr virus latent membrane protein 1 represses p53-mediated DNA repair and transcriptional activity. Oncogene 24, 2635–2646 (2005). https://doi.org/10.1038/sj.onc.1208319

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