Venkatesan, Subramanian;
(2021)
Investigation of APOBEC3 regulation and function in cancer.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The APOBEC3 gene family of cytosine deaminases has a diverse range of functions which have not been fully elucidated. The human APOBEC3 gene family is thought to be involved in the restriction of viruses as well as retrotransposons, however recently the importance of APOBEC3 has been highlighted in oncology with the discovery of an APOBEC3-mediated mutational signature in cancer genomes. Nevertheless, the regulation of APOBEC3 gene expression and APOBEC3-mediated mutagenesis has not been fully elucidated and it is a focus of this thesis. In this thesis, APOBEC3 was primarily studied in the context of breast cancer and non-small cell lung cancer. Here, I link endogenous and exogenous sources of replication stress with driving APOBEC3B gene expression and activity. Conversely, alleviating replication stress by nucleoside supplementation, inhibiting oncogenic signalling or inhibiting DNA replication stress signalling, reduced APOBEC3B gene expression and activity. Furthermore, I investigated whether cigarette carcinogens could induce APOBEC3 transcription, however I was unable to find a general mechanism through which cigarette carcinogens induce APOBEC3 transcription and promote APOBEC3-mediated mutagenesis. Lastly, I showed that specific APOBEC3 genes are upregulated early in tumourigenesis during dysplasia. Additionally, I show that APOBEC3B promotes chromosomal instability through incomplete replication of genomic DNA. Our data suggest that APOBEC3B promotes copy number heterogeneity in addition to point mutation heterogeneity in the early stages of cancer development. Elucidating the regulation and function of APOBEC3 in cancer, will further our understanding of cancer initiation, progression and treatment resistance.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Investigation of APOBEC3 regulation and function in cancer |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10132631 |
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