Adenovirus E4 34k and E4 11k inhibit double strand break repair and are physically associated with the cellular DNA-dependent protein kinase.
The adenovirus oncoproteins E4 34k and E4 11k, the products of E4 open reading frames 6 and 3, respectively, individually prevent the formation of concatemers of the linear viral genome in infected cells. We show here that genome concatenation in E4 mutant-infected cells requires the cellular DNA-dependent protein kinase (DNA PK) and that E4 34k inhibits V(D)J recombination, a normal cellular process that is also dependent on DNA PK. We further show that both E4 34k and E4 11k coimmunoprecipitate with DNA PK. These observations indicate that E4 products block formation of concatemers of the viral genome by inhibiting DNA PK-dependent double strand break repair and suggest that they act by forming a physical complex with DNA PK. DNA PK also participates in activation of p53 DNA-binding activity by DNA damage. By inhibiting DNA PK function, E4 products may block p53 activation in response to the products of viral DNA replication and thus provide a new mechanism to prevent apoptosis of infected cells.
Boyer
J
J
Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Public Health, Baltimore, Maryland 21205, USA.
Rohleder
K
K
Ketner
G
G
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism*; D017504:Adenovirus E4 Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D004279:DNA, Viral / Q000235:genetics; D051747:DNA-Activated Protein Kinase; D004268:DNA-Binding Proteins; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D016679:Genome, Viral; D006801:Humans; D008954:Models, Biological; D008970:Molecular Weight; D009154:Mutation; D009687:Nuclear Proteins; D011233:Precipitin Tests; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic / Q000235:genetics; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D017504:Adenovirus E4 Proteins; D004279:DNA, Viral; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases