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Title: ATM signalling and oxidative DNA damage in cancer
Author: Foster, Hanna
ISNI:       0000 0004 7660 0248
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available