|M.Sc Student||Shalata Hassan|
|Subject||Study of the Contribution of the Adenovirus E4orf4 Protein|
to Virus-Host Cell Interactions
|Department||Department of Medicine||Supervisor||Professor Tamar Kleinberger|
|Full Thesis text - in Hebrew|
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. 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 when E4orf4 is expressed alone1.
Studies of the underlying mechanisms indicate that E4orf4 is recruited rapidly to damage sites and associates with DNA damage sensors, such as DNA-PK. Recruitment to the damage sites requires DNA damage sensor activity. During virus infection, DNA-PK activity appears to contribute to E4orf4 function in the DDR at early times of infection and is inhibited at later times. Inhibition of DNA-PK by drugs enhances adenovirus replication, as we have shown previously for DNA damage transducers including ATM and ATR, but a delay in DNA-PK inhibition enhances virus replication even further. The results indicate that the functional interaction between E4orf4 and DNA PK has a dual role that is temporally regulated and that inhibition of DNA damage signaling at various levels by E4orf4 contributes to adenovirus replication.
1Brestovitsky A, Nebenzahl-Sharon K, Kechker P, Sharf R, Kleinberger T. PLoS Pathog. 2016 Feb 11;12(2):e1005420. doi: 10.1371/journal.ppat.1005420. eCollection 2016 Feb 11.