UMMS Affiliation
Department of Medicine, Department of Infectious Diseases and Immunology; Department of Microbiology and Physiological Systems; Program in Immunology and Virology
Publication Date
2011-05-12
Document Type
Article
Subjects
DNA Damage; E2F1 Transcription Factor; Cytomegalovirus
Disciplines
Genetics and Genomics | Immunology and Infectious Disease | Life Sciences | Medicine and Health Sciences
Abstract
DNA 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.
Rights and Permissions
Copyright: © 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.
DOI of Published Version
10.1371/journal.ppat.1001342
Source
E 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
Journal/Book/Conference Title
PLoS pathogens
Related Resources
PubMed ID
21589897
Repository Citation
E. X, Pickering MT, Debatis ME, Castillo JP, Lagadinos A, Wang S, Lu S, Kowalik TF. (2011). An E2F1-mediated DNA damage response contributes to the replication of human cytomegalovirus. Open Access Articles. https://doi.org/10.1371/journal.ppat.1001342. Retrieved from https://escholarship.umassmed.edu/oapubs/2347
Included in
Genetics and Genomics Commons, Immunology and Infectious Disease Commons, Medicine and Health Sciences Commons
Comments
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.