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CC BY V4.0, Open Access
Dissertation
INVESTIGATING CROSS-SPECIES ACTIVITY AND REGULATION OF APOBEC3A
Washington State University
Doctor of Philosophy (PhD), Washington State University
07/2024
DOI:
https://doi.org/10.7273/000007035
Abstract
DNA damage within our cells can be caused by endogenous and exogenous sources. When these lesions are not accurately repaired, it can lead to permanent DNA changes in the form of mutations. Over time an accumulation of mutations, especially those within tumor suppressor genes and proto-oncogenes in a cell’s DNA can lead to the development of cancer and additional mutations that result in metastases and therapeutic resistance. Off-target APOBEC cytidine deaminase activity on genomic DNA is a common endogenous source of mutations in cancer cells. APOBEC3 genes primarily function in the restriction of viral replication, however APOBEC-induced signature mutations, characterized by C-to-T or C-to-G mutations within TCA and TCT sequences, are found in over 50% of sequenced tumor samples across multiple cancer types. Of the 11 APOBECs, APOBEC3A (A3A) has been identified as the main contributor to APOBEC mutations.
It is unknown what processes lead to an increase in APOBEC-induced mutations observed in cancer cells compared to healthy cells, thus we sought to understand what regulatory mechanisms control APOBEC levels and activity within cells. In this dissertation we investigate how dysregulation of the ubiquitin-proteasome system influences A3A physiology in cells. Treatment of various types of cancer cells with clinically used proteasome inhibitors consistently induced increased A3A mRNA and protein levels and led to higher cytidine deamination activity. Importantly, we found that elevated A3A from blocking proteasome function can result in DNA damage. Separately, as APOBEC mutagenesis has only been reported in human tumors we sought to test if APOBECs in non-primate species are also capable of producing mutations that may contribute to cancer. We examined the cytidine deaminase activity and substrate selectivity of various A3A orthologs compared to human A3A and connected our findings to residue and predicted structural differences. We found that canine and equine A3A orthologs are less capable of producing mutations than human A3A, which led to the conclusion that APOBEC-induced mutations are likely less common in non-primate cancers and that elevated APOBEC mutagenesis in cancer may be a primate specific phenomenon. We hope the data presented contributes to an understanding of the mechanisms that influence APOBEC mutations in cancer and how APOBEC activity on genomic DNA may
vary between species affected by similar cancers.
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Details
- Title
- INVESTIGATING CROSS-SPECIES ACTIVITY AND REGULATION OF APOBEC3A
- Creators
- Margo Coxon
- Contributors
- Steven A. Roberts (Chair)John J Wyrick (Committee Member)Chengtao Her (Committee Member)Bronwyn Gunn (Committee Member)Nicolas Villarino (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
- 176
- Identifiers
- 99901152216501842
- Language
- English
- Resource Type
- Dissertation