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

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Temple University

1. McDevitt, Shane. Mechanistic Studies of Double-strand Break Repair Factors RAD52 and DNA Polymerase Theta.

Degree: PhD, 2018, Temple University

Biomedical Sciences

Small molecule disruption of RAD52 rings as a mechanism for precision medicine in BRCA deficient cancers Suppression of RAD52 causes synthetic lethality in BRCA deficient cells. Yet pharmacological inhibition of RAD52, which binds single-strand DNA (ssDNA) and lacks enzymatic activity, has not been demonstrated. Here, we identify the small molecule 6-hydroxy-DL-dopa (6-OH-dopa) as a major allosteric inhibitor of the RAD52 ssDNA binding domain. For example, we find that multiple small molecules bind to and completely transform RAD52 undecamer rings into dimers, which abolishes the ssDNA binding channel observed in crystal structures. 6-OH-dopa also disrupts RAD52 heptamer and undecamer ring superstructures, and suppresses RAD52 recruitment and recombination activity in cells with negligible effects on other double-strand break repair pathways. Importantly, we show that 6-OH-dopa selectively inhibits the proliferation of BRCA deficient cancer cells, including those obtained from leukemia patients. Taken together, these data demonstrate small molecule disruption of RAD52 rings as a promising mechanism for precision medicine in BRCA deficient cancers. How RNA transcripts coordinate DNA recombination and repair Genetic studies in yeast indicate that RNA transcripts facilitate homology-directed DNA repair in a manner that is dependent on RAD52. The molecular basis for so-called RNA-DNA repair, however, remains unknown. Using reconstitution assays, we demonstrate that RAD52 directly cooperates with RNA as a sequence-directed ribonucleoprotein complex to promote two related modes of RNA-DNA repair. In a RNA-bridging mechanism, RAD52 assembles recombinant RNA-DNA hybrids that coordinate synapsis and ligation of homologous DNA breaks. In a RNA-templated mechanism, RAD52 mediated RNA-DNA hybrids enable reverse transcription dependent RNA-to-DNA sequence transfer at DNA breaks that licenses subsequent DNA recombination. Notably, we show that both mechanisms of RNA-DNA repair are promoted by transcription of a homologous DNA template in trans. In summary, these data elucidate how RNA transcripts cooperate with RAD52 to coordinate homology-directed DNA recombination and repair in the absence of a DNA donor, and demonstrate a direct role for transcription in RNA-DNA repair. Characterization of DNA polymerase θ as a reverse transcriptase RNA-to-DNA sequence has been observed in human cells, but how the phenomena occurs remains unknown. Multiple lines of evidence suggest putative reverse transcriptase (RT) activity as a potential mechanism for how RNA sequence can alter chromosomal DNA, but the source of this RT remains unknown. Here, we have identified that the unique A-family DNA polymerase theta (Polθ) displays robust RT activity, a characteristic not found in any other human polymerase tested from the A, B, X, and Y families. We propose that Polθ may be responsible for the observed RT activity in human cells.

Temple University – Theses

Advisors/Committee Members: Pomerantz, Richard;, Tempera, Italo, Skorski, Tomasz, Johnson, Neil, Yan, Hong;.

Subjects/Keywords: Molecular biology; Biochemistry;

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

APA (6th Edition):

McDevitt, S. (2018). Mechanistic Studies of Double-strand Break Repair Factors RAD52 and DNA Polymerase Theta. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,518019

Chicago Manual of Style (16th Edition):

McDevitt, Shane. “Mechanistic Studies of Double-strand Break Repair Factors RAD52 and DNA Polymerase Theta.” 2018. Doctoral Dissertation, Temple University. Accessed September 20, 2020. http://digital.library.temple.edu/u?/p245801coll10,518019.

MLA Handbook (7th Edition):

McDevitt, Shane. “Mechanistic Studies of Double-strand Break Repair Factors RAD52 and DNA Polymerase Theta.” 2018. Web. 20 Sep 2020.

Vancouver:

McDevitt S. Mechanistic Studies of Double-strand Break Repair Factors RAD52 and DNA Polymerase Theta. [Internet] [Doctoral dissertation]. Temple University; 2018. [cited 2020 Sep 20]. Available from: http://digital.library.temple.edu/u?/p245801coll10,518019.

Council of Science Editors:

McDevitt S. Mechanistic Studies of Double-strand Break Repair Factors RAD52 and DNA Polymerase Theta. [Doctoral Dissertation]. Temple University; 2018. Available from: http://digital.library.temple.edu/u?/p245801coll10,518019


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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