Adenoviruses (Ad) are everywhere, and while they pose limited threat in individuals with healthy immune systems, they cause significant disease burden in immunocompromised patients. A new study describes a mechanism by which the virus interferes with the host’s ability to detect and eliminate virus intruders.
The cellular DNA damage response (DDR) network interprets the presence of replicating viral DNA genomes as DNA damage and strives to repair it, leading to inhibition of virus replication. Many DNA viruses, including adenovirus, evolved mechanisms to inhibit the DDR, thus increasing the efficiency of virus replication. In this study we identify a novel mechanism used by adenovirus to inhibit the DDR. The viral E4orf4 protein, together with its cellular partner PP2A phosphatase, inhibits damage signaling by reducing phosphorylation of proteins belonging to different DDR branches. Thus inhibition of the DDR by E4orf4 contributes both to virus replication efficiency and to E4orf4-induced cancer cell killing.
E4orf4 employs a novel mechanism to inhibit the DDR, which improves Ad replication and may contribute to induction of cancer-specific cell death by the virus protein. Investigation of this novel mechanism may provide a better understanding of the DDR that is targeted by E4orf4 and required for successful application of a combinatorial treatment of cancer. Understanding the E4orf4 role in inhibition of the DDR may contribute to the development of new anti-viral and anti-cancer treatments.
The Adenovirus E4orf4 Protein Provides a Novel Mechanism for Inhibition of the DNA Damage Response. (2016) PLoS Pathog 12(2): e1005420. doi:10.1371/journal.ppat.1005420
The DNA damage response (DDR) is a conglomerate of pathways designed to detect DNA damage and signal its presence to cell cycle checkpoints and to the repair machinery, allowing the cell to pause and mend the damage, or if the damage is too severe, to trigger apoptosis or senescence. Various DDR branches are regulated by kinases of the phospha- tidylinositol 3-kinase-like protein kinase family, including ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR). Replication intermediates and linear double- stranded genomes of DNA viruses are perceived by the cell as DNA damage and activate the DDR. If allowed to operate, the DDR will stimulate ligation of viral genomes and will inhibit virus replication. To prevent this outcome, many DNA viruses evolved ways to limit the DDR. As part of its attack on the DDR, adenovirus utilizes various viral proteins to cause degradation of DDR proteins and to sequester the MRN damage sensor outside virus repli- cation centers. Here we show that adenovirus evolved yet another novel mechanism to inhibit the DDR. The E4orf4 protein, together with its cellular partner PP2A, reduces phos- phorylation of ATM and ATR substrates in virus-infected cells and in cells treated with DNA damaging drugs, and causes accumulation of damaged DNA in the drug-treated cells. ATM and ATR are not mutually required for inhibition of their signaling pathways by E4orf4. ATM and ATR deficiency as well as E4orf4 expression enhance infection efficiency. Furthermore, E4orf4, previously reported to induce cancer-specific cell death when expressed alone, sensitizes cells to killing by sub-lethal concentrations of DNA damaging drugs, likely because it inhibits DNA damage repair. These findings provide one explanation for the can- cer-specificity of E4orf4-induced cell death as many cancers have DDR deficiencies leading to increased reliance on the remaining intact DDR pathways and to enhanced susceptibility to DDR inhibitors such as E4orf4. Thus DDR inhibition by E4orf4 contributes both to the effi- ciency of adenovirus replication and to the ability of E4orf4 to kill cancer cells.