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Journal of Virology, August 2008, p. 8124-8137, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00430-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Epstein-Barr Virus Latent Membrane Protein 1 Represses DNA Repair through the PI3K/Akt/FOXO3a Pathway in Human Epithelial Cells{triangledown}

Yi-Ren Chen,1 Ming-Tsan Liu,3 Yu-Ting Chang,2 Chung-Chun Wu,2 Chi-Yuan Hu,2 and Jen-Yang Chen1,2*

Graduate Institute of Microbiology, College of Medicine, National Taiwan University, 7F, No. 1, Section 1, Ren-Ai Road, Taipei City 10051, Taiwan,1 National Health Research Institutes, No.35, Keyan Road, Zhunan Town, Miaoli County 35053, Taiwan,2 Centers for Disease Control, No. 6, Linsen S. Road, Taipei City 10050, Taiwan3

Received 27 February 2008/ Accepted 23 May 2008

Latent membrane protein 1 (LMP1), an Epstein-Barr virus (EBV) oncoprotein, mimics a constitutively activated tumor necrosis factor receptor and activates various signaling pathways, including phosphatidylinositol 3-kinase (PI3K)/Akt. LMP1 is essential for EBV-mediated B-cell transformation and is sufficient to transform several cell lines. Cellular transformation has been associated strongly with genomic instability, while DNA repair plays an important role in maintaining genomic stability. Previously, we have shown that LMP1 represses DNA repair by the C-terminal activating region 1 (CTAR1) in human epithelial cells. In the present study, we demonstrate that the PI3K/Akt pathway is required for LMP1-mediated repression of DNA repair. Through the LMP1/PI3K/Akt pathway, FOXO3a, which can induce DNA repair, is inactivated because of phosphorylation and relocalization. Expression of a constitutively active FOXO3a mutant can rescue LMP1-mediated repression of DNA repair. Furthermore, LMP1 can decrease the expression of DNA damage-binding protein 1 (DDB1), which functions in nucleotide excision repair, through the PI3K/Akt/FOXO3a pathway. LMP1-mediated repression of DNA repair is restored by DDB1, although only partially. These results suggest that LMP1 triggers the PI3K/Akt pathway to inactivate FOXO3a and decrease DDB1, which can lead to repression of DNA repair and may contribute to genomic instability in human epithelial cells.

* Corresponding author. Mailing address: National Health Research Institutes, No. 35, Keyan Road, Zhunan Town, Miaoli County, Taiwan. Phone: (886) 37-246166, ext. 31718. Fax: (886) 37-586463. E-mail: cjy{at}nhri.org.tw

{triangledown} Published ahead of print on 4 June 2008.

Journal of Virology, August 2008, p. 8124-8137, Vol. 82, No. 16
0022-538X/08/$08.00+0     doi:10.1128/JVI.00430-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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