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ATM signalling and oxidative DNA damage in cancer

Foster, Hanna; (2018) ATM signalling and oxidative DNA damage in cancer. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Unresolved DNA damage can lead to genome instability and carcinogenesis. ATM, a protein kinase mutated in ataxia-telangiectasia, plays a key role in protecting cells from deleterious effects of double-strand breaks, replication stress and oxidative stress. ATMIN is an ATM cofactor and transcription factor, but mechanisms regulating ATMINmediated ATM signalling are unclear. I demonstrate that ATMIN is able to form homooligomers and identify an ATMIN oligomerisation mutant, which shows a clear separation of functions. ATMIN homo-oligomerisation is required for ATMIN function as a transcription factor, but is dispensable for its interaction with ATM in basal and canonical ATM signalling. Additionally, I demonstrate that ATMIN homo-oligomerisation is necessary for oxidative stress-induced ATM signalling. ATM is frequently mutated in lung cancer patients, however the biological role of ATM in the development of lung cancer remains largely unknown. Through this work, I show that mono- and bi-allelic loss of ATM, or its cofactor ATMIN, accelerates the initiation and progression of lung adenocarcinoma (LUAD) in a murine cancer model, driven by lungspecific activation of oncogenic KRasG12D and bi-allelic deletion of Trp53. In addition, I reveal a loss of ATM protein expression in one third of human LUAD biopsies, and a correlation between low ATM or ATMIN gene expression and reduced overall survival in lung adenocarcinoma patients. Oxidative DNA damage represents an inevitable consequence of cellular metabolism and has been implicated, to varying degrees, in development of different cancer types. 8-oxoG is one of the most prevalent oxidative DNA lesions, but available detection methods do not allow precise genome-wide mapping of its distribution. This study introduces ODP-Seq, a novel 8-oxoG detection technique, which has been implemented as a collaborative project. I also show that potassium bromate-induced intestinal tumorigenesis in repair-deficient animals could be used as a model to study the role of oxidative DNA damage in cancer.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: ATM signalling and oxidative DNA damage 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 2018. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/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 > Provost and Vice Provost Offices
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 Life Sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10064501
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