The Adenovirus genome is structured as a linear double-stranded DNA molecule covalently linked to terminal protein at each end and at times during an infection and within the virion, coated by viral protein VII. The double-strand break repair proteins can perceive this DNA structure as a double-strand break and elicit a checkpoint signaling response and DNA repair program that results in genome concatenation unless the DSBR response is inactivated in some way. The viral proteins, E4 ORF6 and E1B 55K, form an E3 ubiquitin ligase complex with other cellular proteins to cause the specific degradation of several known cellular substrates. One of these substrates is the Mre11 protein of the MRN complex, which is the sensor of DSBs. Inactivation of this complex is necessary for efficient viral DNA replication and a productive infection to occur. I have shown that E4-ORF6/E1B-55K-dependent degradation of Mre11 occurs prior to the onset of viral DNA accumulation. A functional assay was also performed to show that the DSBR response is inhibited to such a degree during infection that a checkpoint signaling response is not elicited even after newly-introduced DSBs are formed from ionizing radiation. TP was also found still attached to mutant genomes that are unable to inhibit the MRN complex at a time when checkpoint signaling was induced. This suggests that TP is not the protective factor that prevents checkpoint signaling during the immediate early phase of viral infection from the DSBR response. It also suggests that degradation of the termini of the genome, which contains the origins of replication, and which would cleave TP off, is not an important factor for the viral DNA replication block. Finally, it is also shown that viral protein VII may serve as the protective factor early during infection and that with higher levels of transcription, causing the release of VII, the MRN complex can recognize the DNA ends and elicit a checkpoint signaling response. It is also proposed that the formation of these complexes on the genomes can prevent the formation of pre-initiation complexes required for viral DNA replication.