Show simple item record

dc.contributor.advisorTempera, Italo
dc.creatorLupey-Green, Lena Nicole
dc.date.accessioned2020-10-27T15:14:18Z
dc.date.available2020-10-27T15:14:18Z
dc.date.issued2017
dc.identifier.urihttp://hdl.handle.net/20.500.12613/1791
dc.description.abstractEpstein Barr virus (EBV) is a gammaherpesvirus that infects more than 95% of the human population worldwide. EBV latent infection of B cells is associated with a variety of lymphomas and epithelial cancers and accounts for approximately 1% of all human cancers. The EBV genome persists in infected host cells as a chromatinized episome and is subject to chromatin-mediated regulation. Binding of the host insulator protein CTCF to the EBV genome has an established role in maintaining viral latency type, and in other herpesviruses, loss of CTCF binding at specific regions correlates with viral reactivation. CTCF is post-translationally modified by the host enzyme PARP1, which can affect CTCF’s insulator activity, DNA binding capacity, and ability to form chromatin loops. Both PARP1 and CTCF have been implicated in the regulation of EBV latency and lytic reactivation. Here, we show that PARP activity regulates CTCF in type III EBV latency to maintain latency type-specific gene expression. Further, PARP1 supports chromatin looping between the OriP enhancer and other regions throughout the EBV genome. Further, we show that CTCF is not involved in EBV lytic reactivation, although it is known to restrict reactivation in other herpesviruses. Both PARP activity and PARP1 binding function to restrict EBV lytic reactivation in response to physiological lytic induction. Overall, we show that PARP1 has specific functions throughout the EBV genome, and CTCF function is specifically regulated by PARP activity at specific loci. Taken together, we suggest a model in which PARP1 acts as a stress sensor to determine the fate of the virus in the host cell. These data provide a mechanistic understanding of PARP1 function throughout the EBV genome that suggest potential therapeutic application of PARP inhibitors in EBV-associated treatment strategies. We propose two distinct strategies specific to EBV latency type that could target EBV-infected cancer cells beyond the current chemotherapeutic standard-of-care.
dc.format.extent139 pages
dc.language.isoeng
dc.publisherTemple University. Libraries
dc.relation.ispartofTheses and Dissertations
dc.rightsIN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available.
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/
dc.subjectVirology
dc.subjectBiology, Molecular
dc.subjectMicrobiology
dc.subjectCtcf
dc.subjectEpigenetics
dc.subjectEpstein Barr Virus
dc.subjectHerpesvirus
dc.subjectParp1
dc.titlePARP1-MEDIATED EPIGENETIC CONTROL OF LATENCY AND LYTIC REACTIVATION OF THE EPSTEIN BARR VIRUS
dc.typeText
dc.type.genreThesis/Dissertation
dc.contributor.committeememberEngel, Nora
dc.contributor.committeememberPomerantz, Richard
dc.contributor.committeememberSapienza, Carmen
dc.contributor.committeememberSawaya, Bassel E.
dc.description.departmentBiomedical Sciences
dc.relation.doihttp://dx.doi.org/10.34944/dspace/1773
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.description.degreePh.D.
refterms.dateFOA2020-10-27T15:14:18Z


Files in this item

Thumbnail
Name:
LupeyGreen_temple_0225E_13076.pdf
Size:
7.801Mb
Format:
PDF

This item appears in the following Collection(s)

Show simple item record