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.