Epstein-Barr virus (EBV) is a human tumor virus that is etiologically associated with nasopharyngeal and gastric cancer, Burkitt's, Hodgkin's and immunoblastic lymphoma and other human cancers. In all EBVassociated tumors and in normal B cells, the virus remains in a latent state of limited gene expression. The virus must be reactivated into its lytic cycle in order to spread between cells and among individuals. The EBV/Rta protein encoded in the viral BRLF1 gene plays an obligatory role in mediating the switch between latency and lytic cycle gene expression, acting both as a transcription factor and a replication protein. Rta is thus is a key factor in pathogenesis and oncogenesis. Our global objectives are to understand the control of BRLF1 expression, the mechanism of action of Rta and the ways Rta might manipulate expression and localization of cellular proteins. The proposed experiments are derived from many recent publications and extensive preliminary data that investigated control of expression and regulation of activity of EBV/Rta and its homologue KSHV/ORF50. We will address unsolved mysteries: Which cellular proteins regulate expression of Rta? Why do some cells respond to lytic inducing stimuli by expression of Rta while other cells are refractory? How does Rta function both as a transcription factor and replication protein? How does Rta alter the function and localization of key cellular proteins? Accordingly, our specific aims are 1) To determine the capacity and importance of cellular immediate-early proteins, such as early response and orphan nuclear receptor proteins, to activate Rta expression;2) To understand the function of Rta in EBV DNA replication, particularly the role of phosphorylation and regulation of DNA binding;and 3) To delineate the function of Rta in expression, activation and re-Iocalization of the DNA damage response cohesin, SMC1, STAT3 and PolyA binding protein. The proposed studies, utilizing tools of cell biology, biochemistry, molecular genetics, and immunology address both basic questions of control of eukaryotic gene expression that are relevant to cancer and specific unresolved issues about molecular pathogenesis of an important human cancer virus for which there is yet no specific prevention or treatment.

Public Health Relevance

Basic studies of the molecular biology of the Rta protein of Epstein-Barr virus will ultimately lead to enhanced understanding of pathogenesis and improved diagnosis, treatment and prevention of EBV-associated cancers that are of world-wide importance.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Yale University
New Haven
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Guo, Yang Eric; Steitz, Joan A (2014) 3'-Biotin-tagged microRNA-27 does not associate with Argonaute proteins in cells. RNA 20:985-8
Goodwin, Edward C; Motamedi, Nasim; Lipovsky, Alex et al. (2014) Expression of DNAJB12 or DNAJB14 causes coordinate invasion of the nucleus by membranes associated with a novel nuclear pore structure. PLoS One 9:e94322
Cech, Thomas R; Steitz, Joan A (2014) The noncoding RNA revolution-trashing old rules to forge new ones. Cell 157:77-94
Dimaio, Daniel (2014) Is virology dead? MBio 5:e01003-14
Guo, Yang Eric; Riley, Kasandra J; Iwasaki, Akiko et al. (2014) Alternative capture of noncoding RNAs or protein-coding genes by herpesviruses to alter host T cell function. Mol Cell 54:67-79
Carney, Daniel W; Nelson, Christian D S; Ferris, Bennett D et al. (2014) Structural optimization of a retrograde trafficking inhibitor that protects cells from infections by human polyoma- and papillomaviruses. Bioorg Med Chem 22:4836-47
Zhang, Wei; Kazakov, Teymur; Popa, Andreea et al. (2014) Vesicular trafficking of incoming human papillomavirus 16 to the Golgi apparatus and endoplasmic reticulum requires ?-secretase activity. MBio 5:e01777-14
Xie, Mingyi; Steitz, Joan A (2014) Versatile microRNA biogenesis in animals and their viruses. RNA Biol 11:673-81
Park, Richard; El-Guindy, Ayman; Heston, Lee et al. (2014) 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 9:e92593
Guo, Yang Eric; Steitz, Joan A (2014) Virus meets host microRNA: the destroyer, the booster, the hijacker. Mol Cell Biol 34:3780-7

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