title: The Mre11/Rad50/Nbs1 complex limits adeno-associated virus transduction and replication.
abstract: Adeno-associated virus (AAV) is a parvovirus with a small single-stranded DNA genome that relies on cellular replication machinery together with functions supplied by coinfecting helper viruses. The impact of host factors on AAV infection is not well understood. We explored the connection between AAV helper functions supplied by adenovirus and cellular DNA repair proteins. The adenoviral E1b55K/E4orf6 proteins induce degradation of the cellular Mre11 repair complex (MRN) to promote productive adenovirus infection. These viral proteins also augment recombinant AAV transduction and provide crucial helper functions for wild-type AAV replication. Here, we show that MRN poses a barrier to AAV and that the helper function provided by E1b55K/E4orf6 involves MRN degradation. Using a fluorescent method to visualize the viral genome, we show an effect at the viral DNA level. MRN components accumulate at AAV replication centers and recognize the viral inverted terminal repeats. Together, our data suggest that AAV is targeted by MRN and has evolved to exploit adenoviral proteins that degrade these cellular factors.
authors: Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors: Rachel A
authors: RA
authors: Schwartz
authors: Jose Alejandro
authors: JA
authors: Palacios
authors: Geoffrey D
authors: GD
authors: Cassell
authors: Sarah
authors: S
authors: Adam
authors: Mauro
authors: M
authors: Giacca
authors: Matthew D
authors: MD
authors: Weitzman
mesh_terms: D017766:Acid Anhydride Hydrolases; D000256:Adenoviridae / Q000276:immunology* / Q000502:physiology; D017501:Adenovirus E1B Proteins / Q000502:physiology; D017504:Adenovirus E4 Proteins / Q000502:physiology; D018797:Cell Cycle Proteins / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D045643:DNA Repair Enzymes / Q000276:immunology* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000276:immunology* / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D000076228:MRE11 Homologue Protein; D009687:Nuclear Proteins / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D014161:Transduction, Genetic; D014779:Virus Replication / Q000276:immunology / Q000502:physiology*
chemical_list: D017501:Adenovirus E1B Proteins; D017504:Adenovirus E4 Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes