title: Adenovirus core protein VII protects the viral genome from a DNA damage response at early times after infection.
abstract: Adenovirus has a linear, double-stranded DNA genome that is perceived by the cellular Mre11-Rad50-Nbs1 (MRN) DNA repair complex as a double-strand break. If unabated, MRN elicits a double-strand break repair response that blocks viral DNA replication and ligates the viral genomes into concatemers. There are two sets of early viral proteins that inhibit the MRN complex. The E1B-55K/E4-ORF6 complex recruits an E3 ubiquitin ligase and targets MRN proteins for proteasome-dependent degradation. The E4-ORF3 protein inhibits MRN through sequestration. The mechanism that prevents MRN recognition of the viral genome prior to the expression of these early proteins was previously unknown. Here we show a temporal correlation between the loss of viral core protein VII from the adenovirus genome and a gain of checkpoint signaling due to the double-strand break repair response. While checkpoint signaling corresponds to the recognition of the viral genome, core protein VII binding to and checkpoint signaling at viral genomes are largely mutually exclusive. Transcription is known to release protein VII from the genome, and the inhibition of transcription shows a decrease in checkpoint signaling. Finally, we show that the nuclease activity of Mre11 is dispensable for the inhibition of viral DNA replication during a DNA damage response. These results support a model involving the protection of the incoming viral genome from checkpoint signaling by core protein VII and suggest that the induction of an MRN-dependent DNA damage response may inhibit adenovirus replication by physically masking the origins of DNA replication rather than altering their integrity.
authors.affiliation: Department of Molecular Genetics and Microbiology, School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.
authors.forename: Kasey A
authors.initials: KA
authors.lastname: Karen
authors.forename: Patrick
authors.initials: P
authors.lastname: Hearing
mesh_terms: D017766:Acid Anhydride Hydrolases; D000256:Adenoviridae / Q000235:genetics / Q000472:pathogenicity*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D002460:Cell Line; D004249:DNA Damage; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors*; D004279:DNA, Viral / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D054884:Host-Pathogen Interactions; D006801:Humans; D000076228:MRE11 Homologue Protein; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors; D014758:Viral Core Proteins / Q000378:metabolism*; D053586:Virus Internalization; D014779:Virus Replication
chemical_list: D018797:Cell Cycle Proteins; D004279:DNA, Viral; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D014758:Viral Core Proteins; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes