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Title: The role of p53 in the embryonic stem cell response to DNA damage
Author: Corbet, Sula Wendeline
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1999
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The hypothesis that p53 deficiency enhances survival of DNA-damage bearing cells was investigated in embryonic stem (ES) cells with inactivation of one or both endogenous p53 genes. ES cells were treated with a variety of DNA-damaging agents including UV light, γ-radiation and the topoisomerase I and II inhibitors, camptothecin and etoposide. Both topoisomerase inhibitors rapidly induced high levels of apoptosis in wild-type ES cells resulting in loss of most of the cell population within 48 hours. Consistent with results previously obtained from other cell types, the apoptotic response to etoposide was found to be p53-dependent at low doses but at the highest dose used p53-independent pathways became evident. Following UV-C irradiation, p53-protein was rapidly induced in wild-type cells and p53-dependent apoptosis followed within 8 hours, leading to death of the majority of cells within 36 hours. Treatment with ionising radiation led to enhanced expression of p53 but resulted in little induction of apoptosis irrespective of p52 status. Evasion of apoptosis in the short term does not necessarily imply a continued capacity for growth and therefore long term survival, measured by clonogenic potential, was also examined. Following both UV and γ-irradiation, clonogenic survival of p53-null cells was significantly higher than survival of wild-type cells, particularly after high levels of DNA-damage where survival was enhanced more than ten-fold. The data confirm that p53 restricts the numbers of cells bearing mutations that survive DNA damage induced by either agent, albeit by mechanisms that differ.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available