DNA repair mechanisms are essential for maintaining genome integrity following events that damage DNA. These responses are an important defense mechanism in stabilizing the genome and preventing mutations that can lead to cancer. DNA damage responses regulate the repair process itself, inhibit the cell cycle while repair takes place, and if the damage is severe, can induce cells to die by apoptosis. Viruses, including adenovirus, deliver their nucleic acid genomes to the cell, and this can sometimes lead to activation of cellular DNA damage responses. Our broad objectives are to understand how cellular DNA damage responses are 1) induced 2) coordinated to effect downstream processes of repair and cell cycle inhibition, and 3) able to regulate viral DNA replication. We expect our results to identify characteristics and activities of Ad genomes that are important for triggering different aspects of cellular DNA repair responses, and to provide insight into the mechanisms involved in coordinating the initial early DNA repair responses with activation of cellular protein that effect cell cycle inhibition, and "repair" adenovirus genomes by ligating them together to form concatemers. We will also study the ability of DNA damage proteins to interact with viral chromatin and assess the impact this has on viral DNA replication. This is relevant to a general understanding of the mechanisms involved in the initial activation of DNA repair responses, and how they are coordinated with activating downstream responses to maintain genome integrity and prevent the development of cancer cells. The proposed work is also relevant to the impact of DNA damage responses on other genome activities such as DNA replication. The fields encompassed by the project include cancer biology, virus host cell interactions, DNA damage responses, and DNA tumor viruses. The project will provide training for approximately 2 graduate students and 3-4 undergraduate students per year.
Cells must repair many forms of DNA damage to avoid developing mutations or chromosome abnormalities that could result in cancer. Viruses can often be studied as simple model systems that can provide significant insight into complex cellular processes. This project will study the activation and coordination of DNA repair responses during adenovirus infection, to gain insight into the mechanisms involved regulating cellular responses to DNA damage, and preventing the development of cancer cells.
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|Mathew, Shomita S; Bridge, Eileen (2008) Nbs1-dependent binding of Mre11 to adenovirus E4 mutant viral DNA is important for inhibiting DNA replication. Virology 374:11-22|
|Mathew, Shomita S; Bridge, Eileen (2007) The cellular Mre11 protein interferes with adenovirus E4 mutant DNA replication. Virology 365:346-55|
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