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Manipulation of cellular DNA repair by early adenovirus proteins

  • Author(s): Orazio, Nicole Ise
  • et al.
Abstract

After induction of DNA double strand breaks (DSBs) the cellular DNA damage response (DDR) functions to inhibit the cell cycle, allowing for repair of the damage. Adenovirus is a double strand DNA virus that replicates in the host cell nucleus and expresses early proteins to inactivate the DNA damage response in order to prevent the recognition of its viral genome as a cellular DSB. Adenovirus that is deleted for the E4 region cannot inactivate the DNA damage response and consequently the viral genome is recognized as DNA damage and the cellular DNA repair machinery ligates the viral genome into end-to- end concatemers. Adenovirus expresses two proteins from the E4 region E4orf3 and E4orf6 that have been demonstrated to inhibit the DNA damage response. E4orf3 mislocalizes cellular proteins to prevent their accumulation at viral replication centers during infection. The E4orf6 protein interacts with the viral protein E1b55K to mediate degradation of cellular proteins in a proteasome-dependent manner. The research presented in this thesis demonstrates that E4orf3 and E4orf6/E1b55K target specific components of the DDR, and provides insight into the consequences of targeting these components for the virus and for cells. The Mre11-Nbs1- Rad50 (MRN) complex is the main sensor of DNA damage and functions to activate the DDR and promote repair of DSBs. We show that E4orf3 mislocalization of the MRN complex prevents a DNA damage response mediated by the Ataxia- Telangiectasia Mutated Rad3 related (ATR) protein. CtIP and BLM are proteins implicated to function in the DDR and in resection of DSBs. We identified the BLM helicase as a novel target of E1b55K/E4orf6 mediated degradation during infection. We also found that CtIP is required for concatemer formation in vitro and is inhibitory to adenovirus replication. Together, the data presented in this thesis demonstrate that adenovirus infection provides an ideal model system for study of DNA damage response and repair pathways. Our studies not only provide information on the function of cellular proteins during infection, but also can yield insights into broader functions for these cellular proteins in a non-viral contex

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