Dissertation
Post-translational regulation of APOBEC3A in breast cancer
Washington State University
Doctor of Philosophy (PhD), Washington State University
07/2024
DOI:
https://doi.org/10.7273/000007034
Abstract
Cancer is the 2nd leading cause of death in the US and is generally characterized by the accumulation of mutations that activate oncogenes or silence tumor suppressor genes. These mutations are the result of DNA damage with both endogenous and exogenous sources. Mutations that decrease the fidelity of DNA replication or repair machinery promote genome instability, which can promote further mutagenesis. This is especially problematic in tumors where accumulation of new mutations increases the heterogeneity, increasing the risk of clonal populations developing mechanisms for metastasis or evading therapies.
APOBEC mutations contribute significantly to mutagenesis in breast cancer, with APOBEC3A being identified as the primary source of these mutations. The research presented here attempts to further our understanding of how APOBEC3A is regulated in cells and how these mechanisms can become dysregulated in cancer. To do this we have investigated the role that post-translational modifications and protein interactions play in regulating APOBEC3A activity in breast cancer. Our inquiry led us to identify APOBEC3A Lys30 as a target for acetylation in a unique mechanism of regulation within the APOBEC3 subfamily, with inhibitory effects on mutagenic activity. We additionally identified proteins that likely play a role in this process, with data suggesting that both HAT1 and SIRT1 influence APOBEC3 activity in cells. Our investigation into APOBEC3A interactors uncovered the ubiquitin-proteasome system as a negative regulator of APOBEC3A transcription, although the mechanism by which this occurs is still largely uncharacterized. These findings not only offer new targets for early identification of APOBEC3A dysregulation in cancer patients, but we hope will also offer targets for the use of novel therapies.
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Details
- Title
- Post-translational regulation of APOBEC3A in breast cancer
- Creators
- Christopher D. Collins
- Contributors
- Steven A Roberts (Chair)Lisa M Gloss (Committee Member)John J Wyrick (Committee Member)John M Hinz (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
- 183
- Identifiers
- 99901152439201842
- Language
- English
- Resource Type
- Dissertation