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 read ing frames 6 and 3, respectively, individually prevent the formation of con catemers of the linear viral genome in infected cells. We show here that ge nome concatenation in E4 mutant-infected cells requires the cellular DNA-de pendent protein kinase (DNA PK) and that E4 34k inhibits V(D)J recombinatio n, a normal cellular process that is also dependent on DNA PK. We further s how that both E4 34k and E4 11k coimmunoprecipitate with DNA PK. These obse rvations indicate that E4 products block formation of concatemers of the vi ral genome by inhibiting DNA PK-dependent double strand break repair and su ggest 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 in hibiting DNA PK function, E4 products may block p53 activation in response to the products of Viral DNA replication and thus provide a new mechanism t o prevent apoptosis of infected cells. (C) 1999 Academic Press.