The adenovirus E4orf4 protein inhibits the DNA damage response through its association with DNA damage sensors

The adenovirus E4orf4 protein is a multifunctional viral regulator, which contributes to temporal regulation of the progression of viral infection. When expressed alone, E4orf4 induces a caspase-independent mode of programmed cell-death in transformed cells. Oncogenic transformation of primary cells sensitizes them to cell-killing by E4orf4, indicating that study of E4orf4 signaling may have implications for cancer therapy. Protein phosphatase 2A (PP2A) is a major E4orf4 partner, which is required for all known E4orf4 functions.

The cellular DNA damage response (DDR) senses DNA damage and initiates signaling cascades that arrest the cell cycle and repair the damage, or induce apoptosis when the damage is too extensive. Linear double stranded genomes of DNA viruses are recognized by the cell as double strand breaks and therefore activate the DDR. Because “repair” by ligation of viral genomes is inhibitory to virus replication, DNA viruses evolved ways to inhibit the DDR. We have shown that E4orf4, in cooperation with PP2A, provides one of the mechanisms to inhibit DNA damage signaling during adenovirus infection as well as in response to DNA-damaging drugs. This E4orf4 function contributes to the efficiency of virus replication and to induction of cell death. Studies of the underlying mechanisms indicate that E4orf4 is recruited rapidly to damage sites and associates with the DNA damage sensors PARP-1 and DNA-PK. Recruitment to the damage sites depends on DNA damage sensor activity and is required for E4orf4-induced cell death. During infection E4orf4 inhibits PARP-1 activity whereas DNA-PK activity appears to contribute to E4orf4 function at early times of infection and is inhibited only later. Inhibition of PARP-1 and delayed inhibition of DNA-PK by drugs enhance adenovirus replication. The results indicate that inhibition of DNA damage signaling at various levels by E4orf4 contributes to adenovirus replication.