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Title: Investigating the cellular and clinical impact of mutations in non-homologous end-joining proteins
Author: Woodbine, Lisa Jane
ISNI:       0000 0004 2681 6729
Awarding Body: University of Sussex
Current Institution: University of Sussex
Date of Award: 2010
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In this thesis, I have developed reliable methods for diagnosing immune deficient patients with DNA repair defects. I have identified novel mutations in the non-homologous end-joining (NHEJ) proteins Artemis, DNA Ligase IV (LigIV) and XLF, which leads to distinct cellular and clinical phenotypes. In addition, I have characterised a polymorphism in Artemis, in an immune deficient patients, that impacts on Artemis activity and causes cellular radiosensitivity, highlighting the potential contribution of polymorphisms in repair genes on cancer development and radiosensitivity. I have explored the role of the newly identified NHEJ protein XLF, and have provided evidence that it functions in promoting LigIV-XRCC4 re-adenylation following ligation. Exploiting a mouse model system for human LigIV syndrome, I have further investigated the roles of LigIV, and shown that it functions in the repair of oxidative damage in mouse embryonic fibroblasts, and in haematopoietic stem cells and their progenitors. I have also provided evidence for the requirement of key components of the DSB damage response machinery, ATM and Artemis, in the repair of the DSBs induced by low dose rate irradiation in replicating and non-replicating cells. Finally I have provided evidence for the requirement of ATM, Artemis and LigIV in the repair of DSBs that arise endogenously and via oxidative damage. Together this data highlights the roles of NHEJ proteins during development and provides information to aid diagnosis and care of patients.
Supervisor: Not available Sponsor: Not available
Qualification Name: Not available Qualification Level: Doctoral
EThOS ID:  DOI: Not available