Dissertation
Transcriptional regulation of APOBEC3A in breast cancer
Washington State University
Doctor of Philosophy (PhD), Washington State University
2023
DOI:
https://doi.org/10.7273/000005072
Abstract
Our DNA accumulates damage on a daily basis from a number of endogenous and exogenous sources. If this damage is left unrepaired it causes mutations in our genomes that can contribute to the progression of cancer. One such source of endogenous mutations is the family of APOBEC cytidine deaminases. The mutation signature caused by APOBEC proteins is abundant in many cancer types, prompting a need to understand the how and why these proteins contribute to cancer progression.
The research presented here focuses on understanding the mechanisms that drive expression of APOBEC3A (A3A) in breast cancer. We examine mechanisms of regulation that are induced with drug treatments as well as ones that contribute to basal expression in cancer cells. Initially we believed that A3A, like other A3 proteins, would be degraded via the ubiquitin proteasome system. Testing various proteasome inhibitors led us to discovering a highly conserved increase in A3A transcript when preventing general proteasome degradation in breast cancer. We confirmed that this increase in transcript leads to an abundance of catalytically active A3A that is capable of causing damage to the cells. Conversely, we were interested in understanding the factors responsible for activating transcription of A3A at the basal level in breast cancer. We uncovered potential transcription factors by assessing clustering analysis of co-expressed genes as well as by identifying transcription factor binding sites within conserved ATAC-seq peaks from cell line and tumor data. With these results we hope to contribute to a better understood model for how A3A is transcriptionally activated in breast cancer in order to potentially modulate expression of A3A for therapeutic purposes.
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Details
- Title
- Transcriptional regulation of APOBEC3A in breast cancer
- Creators
- Madeline Dennis
- Contributors
- Steven A Roberts (Advisor)John J Wyrick (Committee Member)John M Hinz (Committee Member)Chengtao Her (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- School of Molecular Biosciences
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Publisher
- Washington State University
- Number of pages
- 147
- Identifiers
- 99901019633801842
- Language
- English
- Resource Type
- Dissertation