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Title: Analysis of stem cell genome stability and cancer-associated developmental programmes
Author: Aizeer, Khalid Ibrahim
ISNI:       0000 0004 2713 3997
Awarding Body: Prifysgol Bangor University
Current Institution: Bangor University
Date of Award: 2011
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During the developmental programme, post-meiotic cells, gametes, fuse to form a zygote, which divides and forms embryo stem cells. In complex metazoans, such as humans, these cells proliferate and ultimately differentiate to form the distinct organs of a functioning adult. Genomic instabilities in stem cells, germ line cells and somatic cells can result in cells becoming cancerous and one of the primary oncogenic factors is DNA replication stress. In cancer tissues developmental programmes become deregulated with cells loosing cellular identity and potentially disconnecting from their micro environment and undergoing metastasis to other regions of the body, causing extensive organ failure. Within tumours, there are so called cancer stem cells, cells which may have been the original progenitor cells for the tumour formation, but which are also proposed to be capable of tumour self renewal and may be responsible for therapeutic resistance. The relationship between cancer stem cells, embryo stem cells and how their developmental programmes are regulated and linked to genomic instabilities is very poorly understood. This current study explores the links between genome instability pathwaysand developmental programmes. Firstly, it is known that some meiosis-specific genes which function to drive meiotic chromosomal rearrangements become aberrantly activated in somatic, cancerous tissues. This resulted in the hypothesis that activation of meiotic recombination hotspots might generate regions which become refractory to somatic DNA replication and result in genomic loci with the potential to drive oncogenic rearrangements. Due to the technical difficulties of using mammalian cells, we addressedthis hypothesis in a widely used experimental model eukaryote, the fission yeast. From this work no evidence for the activation of eukaryotic meiotic recombination hotspots under replicative stress conditions could be found. Prior to this work a preliminary study had found that mouse embryo stem cells exhibited a significant sensitivity to the topoisomerase poison camptothesin, relative to full differentiated mouse embryonic fibroblasts. This difference in sensitivity was not observed using other DNA damaging agents tested. Given that camptothecin generates DNA double-strand breaks in a replication-dependent fashion this current study set out to determine whether cells with stem cell characteristic have distinct responses to oncogenic insult which perturbs DNA replication. To explore this in humans the teratocarcinoma cell line NTERA2 was employed as it expresses many of the markers of stem cells/cancer stem cells and can be differentiated in vitroto provide isogenic differentiated and undifferentiated human cells. Studies of sensitivities of human NTERA2 (differentiated vs.undifferentiated) and preliminary analyses of mouse stem cells provides evidence that there are inter-species distinctions and possible subtle mechanistic changes to cancer-suppressing genome stability mechanisms upon cellular differentiation in human cells away from the stem cell state.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available