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
Google Scholar
Right arrow Articles by Nichols, G. J.
Right arrow Articles by Ornelles, D. A.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nichols, G. J.
Right arrow Articles by Ornelles, D. A.

 Previous Article  |  Next Article 

Journal of Virology, June 2009, p. 5987-5998, Vol. 83, No. 12
0022-538X/09/$08.00+0     doi:10.1128/JVI.00091-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Widespread Phosphorylation of Histone H2AX by Species C Adenovirus Infection Requires Viral DNA Replication{triangledown}

Gena J. Nichols,1 Jerome Schaack,2 and David A. Ornelles1*

Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157,1 Department of Microbiology, Program in Molecular Biology, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 804532

Received 14 January 2009/ Accepted 18 March 2009

Adenovirus infection activates cellular DNA damage response and repair pathways. Viral proteins that are synthesized before viral DNA replication prevent recognition of viral genomes as a substrate for DNA repair by targeting members of the sensor complex composed of Mre11/Rad50/NBS1 for degradation and relocalization, as well as targeting the effector protein DNA ligase IV. Despite inactivation of these cellular sensor and effector proteins, infection results in high levels of histone 2AX phosphorylation, or {gamma}H2AX. Although phosphorylated H2AX is a characteristic marker of double-stranded DNA breaks, this modification was widely distributed throughout the nucleus of infected cells and was coincident with the bulk of cellular DNA. H2AX phosphorylation occurred after the onset of viral DNA replication and after the degradation of Mre11. Experiments with inhibitors of the serine-threonine kinases ataxia telangiectasia mutated (ATM), AT- and Rad3-related (ATR), and DNA protein kinase (DNA-PK), the kinases responsible for H2AX phosphorylation, indicate that H2AX may be phosphorylated by ATR during a wild-type adenovirus infection, with some contribution from ATM and DNA-PK. Viral DNA replication appears to be the stimulus for this phosphorylation event, since infection with a nonreplicating virus did not elicit phosphorylation of H2AX. Infected cells also responded to high levels of input viral DNA by localized phosphorylation of H2AX. These results are consistent with a model in which adenovirus-infected cells sense and respond to both incoming viral DNA and viral DNA replication.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1064. Phone: (336) 716-9332. Fax: (336) 716-9928. E-mail: ornelles{at}wfubmc.edu

{triangledown} Published ahead of print on 25 March 2009.

Journal of Virology, June 2009, p. 5987-5998, Vol. 83, No. 12
0022-538X/09/$08.00+0     doi:10.1128/JVI.00091-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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