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Title: MSH2, apoptosis, and carcinogenesis
Author: Toft, Neil John
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1998
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Tumour cells which lack DNA mismatch repair are resistant to the cytotoxic effects of DNA methylating agents and Cisplatin. To address whether this resistance is mediated through loss of an MSH2-dependent apoptotic pathway, the apoptotic response of the murine small intestine to DNA methylating agents and Cisplatin was studied. MSH2 was found to play a significant role in the initiation of apoptosis in vivo. The immediate apoptotic response to these agents was p53-dependent in the first 24 hours, however a smaller p53-independent apoptotic response was observed beyond this point. Mice doubly null for both MSH2 and p53 revealed that this delayed p53-indepdnent response was entirely MSH2-dependent. These results demonstrate the existence of a pathway to apoptosis following DNA methylation which is dependent upon both MSH2 and p53. The DNA repair enzyme O6-Alkylguanine-DNA-alkyltransferase (AGT), which removes potentially mutagenic methyl groups from guanine residues, was found to play no role in modulating the MSH2-dependeent apoptotic response of intestinal cells to methylating agents or Cisplatin, indicating that the rate of removal of methylated bases is not a major factor in the decision to enter this pathway. O6-Benzylguanine, a competitive inhibitor of AGT, prevented the metabolic activation of Dacarbazine probably through the inhibition of cytochrome P450 enzymes. This novel finding has adverse implications towards the potential clinical use of O6-Benzylguanine. The data presented in this thesis demonstrate that MSH2 plays a pivotal role in determining both the apoptotic response and mutation frequency of the murine intestine to methylating DNA damage and suggests that the consequences of MSH2-deficiency may be more significant to the initial stages of carcinogenesis that loss of p53.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available