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Title: The cellular impact of diminished DNA origin licensing capacity and its potential therapeutic exploitation
Author: Zimmerman, Kristin Mara
ISNI:       0000 0004 2735 3973
Awarding Body: University of Sussex
Current Institution: University of Sussex
Date of Award: 2013
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Genomic instability underlies various diseases including cancer. The maintenance of genomic stability requires accurate replication of the genome, proper segregation of duplicated DNA to progeny cells, and the capacity to respond effectively to DNA damage. Early sections of this thesis focus on the response to DNA double-strand breaks (DSBs) within compact regions of chromatin (heterochromatin). Here, methodology was optimised for monitoring the repair of site-specific DSBs within regions likely to be enriched for heterochromatin. This system was exploited to examine the function of the Artemis endonuclease in heterochromatic DSB repair. Later sections focus on factors involved in DNA replication and the response to replication stress. Among the various mechanisms involved in the DNA damage response (DDR) to replication stress, the licensing of excess origins of replication has been proposed to safeguard against replication failure. Here, the impact of diminished origin licensing capacity on the response to replication stress was compared in tumour and non-tumour cell lines. I present findings demonstrating that depletion of origin licensing factors causes hypersensitisation of tumour-derived but not non-tumour cell lines to replication stress-inducing agents. Further, combining diminished origin licensing capacity with depletion of the tumour suppressor, p53, or overexpression of the c-Myc oncogene impairs viability under conditions of replication stress in non-tumour fibroblasts. These findings suggest that tumour cells have a greater reliance on origin licensing capacity, raising the possibility that licensing factors might represent suitable targets for drugbased cancer therapy. Factors involved in replication origin licensing have also been implicated in the establishment of heterochromatin. Here, I examined higher-order chromatin structure and the ionizing radiation (IR)-induced DDR in cells from patients harbouring mutations in origin licensing factors. Findings from these studies provide evidence for the first time that origin licensing complex (ORC)-deficient Meier-Gorlin Syndrome (MGS) may be classified as a disordered chromatin syndrome.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QH0426 Genetics