An E2F1-mediated DNA damage response contributes to the replication of human cytomegalovirus
Pickering, Mary Theresa
Debatis, Michelle E.
Castillo, Jonathan Patrick
Kowalik, Timothy F.
UMass Chan AffiliationsProgram in Immunology and Virology
Department of Microbiology and Physiological Systems
Department of Medicine, Department of Infectious Diseases and Immunology
Document TypeJournal Article
E2F1 Transcription Factor
Genetics and Genomics
Immunology and Infectious Disease
Medicine and Health Sciences
MetadataShow full item record
AbstractDNA damage resulting from intrinsic or extrinsic sources activates DNA damage responses (DDRs) centered on protein kinase signaling cascades. The usual consequences of inducing DDRs include the activation of cell cycle checkpoints together with repair of the damaged DNA or induction of apoptosis. Many DNA viruses elicit host DDRs during infection and some viruses require the DDR for efficient replication. However, the mechanism by which DDRs are activated by viral infection is poorly understood. Human cytomegalovirus (HCMV) infection induces a DDR centered on the activation of ataxia telangiectasia mutated (ATM) protein kinase. Here we show that HCMV replication is compromised in cells with inactivated or depleted ATM and that ATM is essential for the host DDR early during infection. Likewise, a downstream target of ATM phosphorylation, H2AX, also contributes to viral replication. The ATM-dependent DDR is detected as discrete, nuclear gammaH2AX foci early in infection and can be activated by IE proteins. By 24 hpi, gammaH2AX is observed primarily in HCMV DNA replication compartments. We identified a role for the E2F1 transcription factor in mediating this DDR and viral replication. E2F1, but not E2F2 or E2F3, promotes the accumulation of gammaH2AX during HCMV infection or IE protein expression. Moreover, E2F1 expression, but not the expression of E2F2 or E2F3, is required for efficient HCMV replication. These results reveal a novel role for E2F1 in mediating an ATM-dependent DDR that contributes to viral replication. Given that E2F activity is often deregulated by infection with DNA viruses, these observations raise the possibility that an E2F1-mediated mechanism of DDR activation may be conserved among DNA viruses.
SourceE X, Pickering MT, Debatis M, Castillo J, Lagadinos A, et al. (2011) An E2F1-Mediated DNA Damage Response Contributes to the Replication of Human Cytomegalovirus. PLoS Pathog 7(5): e1001342. doi:10.1371/journal.ppat.1001342. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/39551
Co-author Alexander Lagadinos is a student in the Immunology and Virology Program in the Graduate School of Biomedical Sciences (GSBS) at UMass Medical School.
Related ResourcesLink to Article in PubMed
RightsCopyright: © 2011 E et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.