Date of Award
2024
Embargo Period
4-22-2029
Document Type
Thesis
Degree Name
Master of Biomedical Science
Department
Biochemistry and Molecular Biology
College
College of Graduate Studies
First Advisor
David Long
Second Advisor
Jessica Hartman
Third Advisor
Robin Muise-Helmericks
Fourth Advisor
Michael Ostrowski
Abstract
DNA is continually assaulted by various intrinsic and extrinsic agents. To safeguard genome integrity, cells utilize a complex signaling network called the DNA damage response (DDR). The Bromodomain and Extraterminal (BET) protein BRD4 is a chromatin reader that regulates transcription of numerous oncogenes and DNA repair genes by recruiting transcription factors and protein complexes. However, recent studies have revealed a more direct role for BRD4 in the DDR. BRD4 contains two bromodomains that interact with acetylated histones, serving as a scaffold to coordinate transcription and DNA repair by recruiting multiple protein complexes to chromatin, including P-TEFb, SWI/SNF, Rad51, and the MRN complex. We have now shown that the DDR plays an important role in regulating BRD4 function by controlling its interaction with chromatin.
The DNA-dependent protein kinase (DNA-PK) is a signaling kinase that helps to activate the DDR. Using the DNA-PK inhibitor NU7441, I have revealed a novel mechanism of action for the drug that involves BRD4. The overall goal of my thesis is to unravel the mechanism underlying rapid displacement of BRD4 from chromatin by NU7441. Investigating how NU7441 rapidly displaces BRD4 from chromatin sheds light on its off-target effects, as well as that of other related DNA-PK inhibitors. Additionally, by elucidating the interplay between DNA-PK inhibition and BRD4 binding to chromatin, this thesis not only enriches our understanding of how the DDR regulates chromatin biology, but also lays the groundwork for innovative therapeutic strategies targeting BRD4 in cancer therapy.
Recommended Citation
Johnson, Brandon, "Rapid Displacement of BRD4 from Chromatin by the DNA-PK Inhibitor NU7441" (2024). MUSC Theses and Dissertations. 866.
https://medica-musc.researchcommons.org/theses/866
Rights
Copyright is held by the author. All rights reserved.