Epstein-Barr virus latent membrane protein 1 represses p53-mediated DNA repair and transcriptional activity.
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-kappaB activation. Furthermore, blockage of NF-kappaB signalling by IkappaB-DeltaN was shown to abolish the repression of p53 by LMP1, suggesting that LMP1 likely repressed p53 function through the NF-kappaB 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.
Liu
Ming-Tsan
MT
National Health Research Institutes, 3F No. 109, Section 6, Min-Chuan East Road, Taipei 114, Taiwan.
Chang
Yu-Ting
YT
Chen
Shu-Chuan
SC
Chuang
Yu-Chia
YC
Chen
Yi-Ren
YR
Lin
Chang-Shen
CS
Chen
Jen-Yang
JY
D045744:Cell Line, Tumor; D004260:DNA Repair; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D010957:Plasmids; D051996:Transcription Factor RelA; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000378:metabolism*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D051996:Transcription Factor RelA; D016159:Tumor Suppressor Protein p53; D014763:Viral Matrix Proteins