DNA Replication; Oncogenic Viruses; Pediatrics; Phosphorylation; Transcription Factors; Tumor Virus Infections; Epstein-Barr Virus Infections; Infectious Disease Medicine
Discovery to Cure Internship
Our research focuses on the process of Epstein-Barr virus (EBV) lytic DNA replication. Epstein-Barr virus, an oncogenic virus, is associated with lymphomas and carcinomas, such as Burkitt lymphoma and nasopharyngeal carcinoma. The EBV life cycle is divided into two phases, latent and lytic. EBV is predominantly latent. The only route for the virus to amplify and infect new individuals is through activation of its lytic gene expression program. ZEBRA, a viral transcription activator, mediates the switch from the latent to the lytic phase. ZEBRA is also essential for the process of viral DNA replication; it binds to the origin of lytic replication and recruits other components of the replication machinery. In our studies we found that phosphorylation of the EBV ZEBRA protein regulates its capacity to interact with the origin of replication. These studies led us to characterize a novel role for replication proteins in the process of origin recognition. In addition, we have developed various genetic approaches to assess the involvement of other lytic cycleproteins in the process of viral DNA replication. For example, we have recently found that the EBV Rta protein, which serves as a transcription factor, plays an independent role in replicating the endogenous viral genome. Our goal is to delineate the viral and cellular proteins involved in the process of lytic DNA replication and their role in replication. Identifying the major players responsible for viral DNA replication has a strong potential to generate new strategies for the development of antiviral drugs against EBV.
Specialized Terms: DNA replication; Tumor virus; Herpesvirus; Oncogenic; Transcription factor; Replication protein; Phosphorylation; Protein modification; Kinase
Phosphoacceptor site S173 in the regulatory domain of Epstein-Barr Virus ZEBRA protein is required for lytic DNA replication but not for activation of viral early genes.
El-Guindy, A., Heston, L., Delecluse, H.-J., and Miller, G. (2007) Phosphoacceptor site S173 in the regulatory domain of Epstein-Barr Virus ZEBRA protein is required for lytic DNA replication but not for activation of viral early genes.
A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein.
El-Guindy A, Heston L, Miller G. A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. PLoS Pathogens 2010, 6:e1001054.
Full List of PubMed Publications
- Racicot K, Aldo P, El-Guindy A, Kwon JY, Romero R, Mor G: Cutting Edge: Fetal/Placental Type I IFN Can Affect Maternal Survival and Fetal Viral Load during Viral Infection. J Immunol. 2017 Apr 15; 2017 Mar 6. PMID: 28264970
- McKenzie J, Lopez-Giraldez F, Delecluse HJ, Walsh A, El-Guindy A: The Epstein-Barr Virus Immunoevasins BCRF1 and BPLF1 Are Expressed by a Mechanism Independent of the Canonical Late Pre-initiation Complex. PLoS Pathog. 2016 Nov; 2016 Nov 17. PMID: 27855219
- Racicot K, Kwon JY, Aldo P, Abrahams V, El-Guindy A, Romero R, Mor G: Type I Interferon Regulates the Placental Inflammatory Response to Bacteria and is Targeted by Virus: Mechanism of Polymicrobial Infection-Induced Preterm Birth. Am J Reprod Immunol. 2016 Apr; 2016 Feb 19. PMID: 26892235
- McKenzie J, El-Guindy A: Epstein-Barr Virus Lytic Cycle Reactivation. Curr Top Microbiol Immunol. 2015. PMID: 26428377
- El-Guindy A, Lopez-Giraldez F, Delecluse HJ, McKenzie J, Miller G: A locus encompassing the Epstein-Barr virus bglf4 kinase regulates expression of genes encoding viral structural proteins. PLoS Pathog. 2014 Aug; 2014 Aug 28. PMID: 25166506
- Park R, El-Guindy A, Heston L, Lin SF, Yu KP, Nagy M, Borah S, Delecluse HJ, Steitz J, Miller G: Nuclear translocation and regulation of intranuclear distribution of cytoplasmic poly(A)-binding protein are distinct processes mediated by two Epstein Barr virus proteins. PLoS One. 2014; 2014 Apr 4. PMID: 24705134
- El-Guindy A, Ghiassi-Nejad M, Golden S, Delecluse HJ, Miller G: Essential role of Rta in lytic DNA replication of Epstein-Barr virus. J Virol. 2013 Jan; 2012 Oct 17. PMID: 23077295
- El-Guindy A, Heston L, Miller G: A subset of replication proteins enhances origin recognition and lytic replication by the Epstein-Barr virus ZEBRA protein. PLoS Pathog. 2010 Aug 19; 2010 Aug 19. PMID: 20808903
- Daigle D, Megyola C, El-Guindy A, Gradoville L, Tuck D, Miller G, Bhaduri-McIntosh S: Upregulation of STAT3 marks Burkitt lymphoma cells refractory to Epstein-Barr virus lytic cycle induction by HDAC inhibitors. J Virol. 2010 Jan; 2009 Nov 4. PMID: 19889776
- Dela Cruz CS, Viswanathan SR, El-Guindy AS, Shedd D, Miller G: Complex N-linked glycans on Asn-89 of Kaposi sarcoma herpes virus-encoded interleukin-6 mediate optimal function by affecting cytokine protein conformation. J Biol Chem. 2009 Oct 23; 2009 Aug 18. PMID: 19690161
- El-Guindy A, Heston L, Delecluse HJ, Miller G: Phosphoacceptor site S173 in the regulatory domain of Epstein-Barr Virus ZEBRA protein is required for lytic DNA replication but not for activation of viral early genes. J Virol. 2007 Apr; 2007 Jan 10. PMID: 17215287
- Bhaduri-McIntosh S, Landry ML, Nikiforow S, Rotenberg M, El-Guindy A, Miller G: Serum IgA antibodies to Epstein-Barr virus (EBV) early lytic antigens are present in primary EBV infection. J Infect Dis. 2007 Feb 15; 2007 Jan 10. PMID: 17230407
- Miller G, El-Guindy A, Countryman J, Ye J, Gradoville L: Lytic cycle switches of oncogenic human gammaherpesviruses. Adv Cancer Res. 2007. PMID: 17419942
- Heston L, El-Guindy A, Countryman J, Dela Cruz C, Delecluse HJ, Miller G: Amino acids in the basic domain of Epstein-Barr virus ZEBRA protein play distinct roles in DNA binding, activation of early lytic gene expression, and promotion of viral DNA replication. J Virol. 2006 Sep. PMID: 16940523
- El-Guindy AS, Paek SY, Countryman J, Miller G: Identification of constitutive phosphorylation sites on the Epstein-Barr virus ZEBRA protein. J Biol Chem. 2006 Feb 10; 2005 Dec 1. PMID: 16321978
- El-Guindy AS, Miller G: Phosphorylation of Epstein-Barr virus ZEBRA protein at its casein kinase 2 sites mediates its ability to repress activation of a viral lytic cycle late gene by Rta. J Virol. 2004 Jul. PMID: 15220438
- Dela Cruz CS, Lee Y, Viswanathan SR, El-Guindy AS, Gerlach J, Nikiforow S, Shedd D, Gradoville L, Miller G: N-linked glycosylation is required for optimal function of Kaposi's sarcoma herpesvirus-encoded, but not cellular, interleukin 6. J Exp Med. 2004 Feb 16. PMID: 14970177
- El-Guindy AS, Heston L, Endo Y, Cho MS, Miller G: Disruption of Epstein-Barr virus latency in the absence of phosphorylation of ZEBRA by protein kinase C. J Virol. 2002 Nov. PMID: 12388679
- Gradoville L, Kwa D, El-Guindy A, Miller G: Protein kinase C-independent activation of the Epstein-Barr virus lytic cycle. J Virol. 2002 Jun. PMID: 11991990