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You searched for +publisher:"Temple University" +contributor:("Pomerantz, Richard T."). Showing records 1 – 2 of 2 total matches.

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Temple University

1. Lupey-Green, Lena Nicole. PARP1-MEDIATED EPIGENETIC CONTROL OF LATENCY AND LYTIC REACTIVATION OF THE EPSTEIN BARR VIRUS.

Degree: PhD, 2017, Temple University

Biomedical Sciences

Epstein 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.

Temple University – Theses

Advisors/Committee Members: Tempera, Italo;, Engel, Nora, Pomerantz, Richard T., Sapienza, Carmen, Sawaya, Bassel E.;.

Subjects/Keywords: Virology; Molecular biology; Microbiology;

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Lupey-Green, L. N. (2017). PARP1-MEDIATED EPIGENETIC CONTROL OF LATENCY AND LYTIC REACTIVATION OF THE EPSTEIN BARR VIRUS. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,463893

Chicago Manual of Style (16th Edition):

Lupey-Green, Lena Nicole. “PARP1-MEDIATED EPIGENETIC CONTROL OF LATENCY AND LYTIC REACTIVATION OF THE EPSTEIN BARR VIRUS.” 2017. Doctoral Dissertation, Temple University. Accessed September 20, 2020. http://digital.library.temple.edu/u?/p245801coll10,463893.

MLA Handbook (7th Edition):

Lupey-Green, Lena Nicole. “PARP1-MEDIATED EPIGENETIC CONTROL OF LATENCY AND LYTIC REACTIVATION OF THE EPSTEIN BARR VIRUS.” 2017. Web. 20 Sep 2020.

Vancouver:

Lupey-Green LN. PARP1-MEDIATED EPIGENETIC CONTROL OF LATENCY AND LYTIC REACTIVATION OF THE EPSTEIN BARR VIRUS. [Internet] [Doctoral dissertation]. Temple University; 2017. [cited 2020 Sep 20]. Available from: http://digital.library.temple.edu/u?/p245801coll10,463893.

Council of Science Editors:

Lupey-Green LN. PARP1-MEDIATED EPIGENETIC CONTROL OF LATENCY AND LYTIC REACTIVATION OF THE EPSTEIN BARR VIRUS. [Doctoral Dissertation]. Temple University; 2017. Available from: http://digital.library.temple.edu/u?/p245801coll10,463893


Temple University

2. Reed, Katherine Sullivan. Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Cancers.

Degree: PhD, 2018, Temple University

Biomedical Sciences

PARP inhibitors (PARPi) have been used to induce synthetic lethality in BRCA-deficient tumors in clinical trials with limited success due to the development of resistance to PARPi. BRCA-deficient cells are unable to repair DNA double strand breaks by the accurate homologous recombination repair (HR), and therefore rely on alternative DNA repair pathways for survival. We hypothesized that RAD52-mediated DNA repair mechanisms remain active and are thus protecting some PARPi-treated BRCA-deficient tumor cells from apoptosis, and that targeting RAD52 should enhance the synthetic lethal effect of PARPi. We show here that RAD52 inhibitors (RAD52i) attenuated single-strand annealing (SSA) and residual HR activity in BRCA-deficient cells. Simultaneous targeting of PARP1 and RAD52 with small molecule inhibitors or via expression of dominant-negative mutants induced an accumulation of DSBs and selective eradication of BRCA-deficient solid tumor and leukemia cells, while BRCA-proficient cells were unaffected. Parp1-/-Rad52-/- transgenic mice are healthy and indistinguishable from wild-type mice due to the presence of the BRCA-pathway, and Parp1-/-Rad52-/- mice with inducible BRCA1-deficient leukemia displayed significantly prolonged survival when compared to Parp1-/- and Rad52-/- counterparts. Finally, PARPi + RAD52i selectively targeted BRCA1-deficient solid tumors in immunodeficient mice with minimal toxicity to normal cells and tissues which are protected by the BRCA-pathway, indicating minimal side effects. In conclusion, our data indicate that combination treatment of RAD52i and PARPi will significantly improve therapeutic outcome of BRCA-deficient malignancies compared to treatment with PARPi monotherapy, while leaving healthy cells and tissues unharmed.

Temple University – Theses

Advisors/Committee Members: Skorski, Tomasz;, Soprano, Dianne R., Grana-Amat, Xavier, Liebermann, Dan A., Pomerantz, Richard T., Johnson, Neil, Mazin, Alex;.

Subjects/Keywords: Oncology; Cellular biology;

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Reed, K. S. (2018). Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Cancers. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,507327

Chicago Manual of Style (16th Edition):

Reed, Katherine Sullivan. “Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Cancers.” 2018. Doctoral Dissertation, Temple University. Accessed September 20, 2020. http://digital.library.temple.edu/u?/p245801coll10,507327.

MLA Handbook (7th Edition):

Reed, Katherine Sullivan. “Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Cancers.” 2018. Web. 20 Sep 2020.

Vancouver:

Reed KS. Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Cancers. [Internet] [Doctoral dissertation]. Temple University; 2018. [cited 2020 Sep 20]. Available from: http://digital.library.temple.edu/u?/p245801coll10,507327.

Council of Science Editors:

Reed KS. Simultaneous Targeting of PARP1 and RAD52 Triggers Dual Synthetic Lethality in BRCA-Deficient Cancers. [Doctoral Dissertation]. Temple University; 2018. Available from: http://digital.library.temple.edu/u?/p245801coll10,507327

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