Delineating the APOBEC3 enzymes responsible for the APOBEC mutation signature in cancer
2021-08
Loading...
View/Download File
Persistent link to this item
Statistics
View StatisticsJournal Title
Journal ISSN
Volume Title
Title
Delineating the APOBEC3 enzymes responsible for the APOBEC mutation signature in cancer
Authors
Published Date
2021-08
Publisher
Type
Thesis or Dissertation
Abstract
Mutations drive the initiation and progression of cancer. The leading druggable source of mutation in cancer, cytosine deamination by a subset of the nine-membered APOBEC family of DNA deaminase enzymes, leaves a distinct mutation signature on the cancer genome. This signature is characterized as C-to-T and C-to-G mutations in a TCA/T trinucleotide context, and thus APOBEC-dependent mutations can be resolved computationally from other processes of mutation in clinical next-generation tumor sequencing datasets. While specific APOBEC3 (A3) enzymes have been implicated as the main progenitors of this mutation signature (namely, APOBEC3A, APOBEC3B, and APOBEC3H, abbreviated A3A, A3B, and A3H), the literature is full of conflicting data and it is not clear which of these enzymes contributes most prominently, and whether other A3 enzymes may also contribute to mutation in cancer. In this thesis, we aim to definitively characterize the A3 enzymes that can contribute to genomic mutation in a mammalian cell, and potentially be involved in cancer mutagenesis. To accomplish this, we utilized bioinformatic approaches to understand mutational profiles in >1000 cancer cell models, the capacity of individual A3s to generate a cellular damage response and genomic mutation in culture, and the carcinogenic action of APOBECs in multiple animal systems of cancer initiation and progression. Taken together, these analyses indicate that both A3A and A3B have the capacity to generate a mutation signature in mammalian cells, and that A3A has the ability to initiate tumor formation in vivo. These novel advancements in the APOBEC biology field could prove invaluable in the design and implementation of future therapies and diagnostics targeting the A3s in cancer. An understanding of enzyme-specific mutational capacity will improve the development of targeted therapies, which could span to small molecule inhibition of enzymatic activity, synthetic lethal strategies, or immunotherapy-based approaches to selectively kill A3-expressing tumor cells, with the ultimate goal of attenuating or exploiting this mutational process to improve poor clinical outcomes (including drug resistance and metastasis).
Description
University of Minnesota Ph.D. dissertation. August 2021. Major: Microbiology, Immunology and Cancer Biology. Advisor: Reuben Harris. 1 computer file (PDF); vii, 201 pages.
Related to
Replaces
License
Collections
Series/Report Number
Funding information
Isbn identifier
Doi identifier
Previously Published Citation
Suggested citation
Jarvis, Matthew. (2021). Delineating the APOBEC3 enzymes responsible for the APOBEC mutation signature in cancer. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/259732.
Content distributed via the University Digital Conservancy may be subject to additional license and use restrictions applied by the depositor. By using these files, users agree to the Terms of Use. Materials in the UDC may contain content that is disturbing and/or harmful. For more information, please see our statement on harmful content in digital repositories.