Stacy R. Hagemeier, PhD

Research Title: Functions of Epstein-Barr Virus BRRF1-encoded Protein during Lytic Infection

Project Summary: Dr. Stacy Hagemeier’s project was to develop a better understanding of how viral and cellular transcription factors cooperate to determine if Epstein-Barr virus (EBV) infection is latent versus lytic in host cells.   She showed that sumoylation of the EBV BLZF1 immediate-early protein at lysine residue 12 inhibits its transcriptional function and helps to promote viral latency.  Furthermore, she discovered that the EBV-encoded kinase, BLGF4, inhibits BZLF1 sumoylation, thereby promoting lytic reactivation.  Stacy also demonstrated that another lytic EBV protein, BRRF1 (“Na”), promotes viral lytic reactivation by interacting directly with the cellular TRAF2 protein, and promoting its ability to activate the JNK kinase.  In addition, she showed that the lytic-inducing effect of the BRRF1 protein is at least partially mediated through p53 activation.  Perhaps most importantly, Stacy discovered that activation of the DNA damage induced cellular kinase, ATM, is required for the ability of most, if not all, lytic inducing stimuli to reactivate lytic EBV gene expression.  This work, which resulted in multiple publications as outlined below, suggests new mechanisms by which purposeful induction of the lytic form of EBV infection in EBV-positive tumors cell might be therapeutically achieved.