This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Liang, X.
Right arrow Articles by Jung, J. U.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Liang, X.
Right arrow Articles by Jung, J. U.

 Previous Article  |  Next Article 

Journal of Virology, June 2006, p. 5862-5874, Vol. 80, No. 12
0022-538X/06/$08.00+0     doi:10.1128/JVI.02732-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Deregulation of DNA Damage Signal Transduction by Herpesvirus Latency-Associated M2

Xiaozhen Liang,1 Mary T. Pickering,2 Nam-Hyuk Cho,1 Heesoon Chang,1 Michael R. Volkert,2 Timothy F. Kowalik,2 and Jae U. Jung1*

Department of Microbiology and Molecular Genetics and Tumor Virology Division, New England Primate Research Center, Harvard Medical School, One Pine Hill Drive, Southborough, Massachusetts 01772,1 Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, Worcester, Massachusetts 016552

Received 29 December 2005/ Accepted 27 March 2006

Infected cells recognize viral replication as a DNA damage stress and elicit a DNA damage response that ultimately induces apoptosis as part of host immune surveillance. Here, we demonstrate a novel mechanism where the murine gamma herpesvirus 68 ({gamma}HV68) latency-associated, anti-interferon M2 protein inhibits DNA damage-induced apoptosis by interacting with the DDB1/COP9/cullin repair complex and the ATM DNA damage signal transducer. M2 expression constitutively induced DDB1 nuclear localization and ATM kinase activation in the absence of DNA damage. Activated ATM subsequently induced Chk activation and p53 phosphorylation and stabilization without eliciting H2AX phosphorylation and MRN recruitment to foci upon DNA damage. Consequently, M2 expression inhibited DNA repair, rendered cells resistant to DNA damage-induced apoptosis, and induced a G1 cell cycle arrest. Our results suggest that {gamma}HV68 M2 blocks apoptosis-mediated intracellular innate immunity, which might ultimately contribute to its role in latent infection.

* Corresponding author. Mailing address: Tumor Virology Division, New England Primate Research Center, 1 Pine Hill Drive, Southborough, MA 01772. Phone: (508) 624-8083. Fax: (508) 786-1416. E-mail: jae_jung{at}hms.harvard.edu.

Journal of Virology, June 2006, p. 5862-5874, Vol. 80, No. 12
0022-538X/06/$08.00+0     doi:10.1128/JVI.02732-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • DeZalia, M., Speck, S. H. (2008). Identification of Closely Spaced but Distinct Transcription Initiation Sites for the Murine Gammaherpesvirus 68 Latency-Associated M2 Gene. J. Virol. 82: 7411-7421 [Abstract] [Full Text]  
  • Forrest, J. C., Speck, S. H. (2008). Establishment of B-Cell Lines Latently Infected with Reactivation-Competent Murine Gammaherpesvirus 68 Provides Evidence for Viral Alteration of a DNA Damage-Signaling Cascade. J. Virol. 82: 7688-7699 [Abstract] [Full Text]  
  • Herskowitz, J. H., Siegel, A. M., Jacoby, M. A., Speck, S. H. (2008). Systematic Mutagenesis of the Murine Gammaherpesvirus 68 M2 Protein Identifies Domains Important for Chronic Infection. J. Virol. 82: 3295-3310 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»