My long-term goal is to understand the relationship between regulatory functions in the nucleus and the replication of human cytomegalovirus (HCMV) and other DNA viruses. This project examines the host response to HCMV infection relating to """"""""genomic stress"""""""", in particular the cellular DNA damage response, and how this response affects HCMV replication. It is known that HCMV infected cells result in a p53 response, whose function is apparently thwarted by IE2 binding. However, the event(s) that leads to the initial host attempt to activate p53 are not understood. We find that the kinase encoded by the ataxia telangiectasia mutated (Atm) gene is activated and phosphorylates p53 during infection. Atm is usually activated in response to genomic stresses such as DNA damage. Once activated, Atm signals proliferation checkpoints and stimulates DNA repair/recombination functions. Given these profound effects associated with Atm signaling, I hypothesize that the event(s) responsible for Atm activation and subsequent signaling affect the ability of HCMV to replicate. Contrary to the role activated Atm normally plays in blocking DNA synthesis, our preliminary results suggest that Atm is required for optimal HCMV replication. Thus it appears that HCMV activates a nuclear stress response in cells and then uses it to facilitate virus replication. In this application, I propose to determine how Atm is activated and its role in modulating HCMV replication, and to identify the event(s) responsible for Atm activation and determine their role in HCMV replication. A result of this research will be the identification of new potential targets for the treatment of cytomegalovirus infections. Future work will determine whether other viruses active and require the same pathways for replication and possibly expand the list of viruses that might be inhibited by targeting these pathways.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Virology - B Study Section (VIRB)
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Beisel, Christopher E
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University of Massachusetts Medical School Worcester
Schools of Medicine
United States
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E, Xiaofei; Savidis, George; Chin, Christopher R et al. (2014) A novel DDB2-ATM feedback loop regulates human cytomegalovirus replication. J Virol 88:2279-90
Xiaofei, E; Stadler, Bradford M; Debatis, Michelle et al. (2012) RNA interference-mediated targeting of human cytomegalovirus immediate-early or early gene products inhibits viral replication with differential effects on cellular functions. J Virol 86:5660-73
Bhattacharjee, Bornali; Renzette, Nicholas; Kowalik, Timothy F (2012) Genetic analysis of cytomegalovirus in malignant gliomas. J Virol 86:6815-24
E, Xiaofei; Pickering, Mary T; Debatis, Michelle et al. (2011) An E2F1-mediated DNA damage response contributes to the replication of human cytomegalovirus. PLoS Pathog 7:e1001342
Pickering, M T; Stadler, B M; Kowalik, T F (2009) miR-17 and miR-20a temper an E2F1-induced G1 checkpoint to regulate cell cycle progression. Oncogene 28:140-5