The regulation of the genome by the epigenetic modifications of DNA methylation and histone modification is increasingly recognized as a vital factor in the development, physiology and pathology of vertebrates. There is mounting evidence suggesting that both aberrant DNA methylation and histone modifications are common events in cancer. This has lead to the establishment of both DNMTs and HDACs as important targets in cancer therapy. There are currently several clinical trials that are testing inhibitors of both DNMTs and HDACs as anticancer agents. This thesis attempts to understand the roles that DNMT1 and HDAC1 play in the regulation of gene expression and epigenomic inheritance. In the first chapter, we examined the effects of DNMT1 inhibitors on gene expression and found that DNMT1 can regulate gene expression independent of its DNA methyltransferase activity. This novel role of DNMT1 has challenged a widely accepted theory that the mechanism of DNMT1 inhibitors involves inhibition of the catalytic activity of DNMT1, thus leading to demethylation and reexpression of tumor suppressors previously silenced by methylation. In chapter 2, we further examined different roles of DNMT1. We showed that different DNMT1 inhibitors inhibit different DNMT1 functions and produce different effects on gene expression. Our data suggests that inhibition of DNMT1 enzymatic activity can produce serious long-term effects as a result of massive non-selective demethylation of the genome. In contrast, reduction of DNMT1 levels was shown to result in a rapid arrest of cell growth, limited demethylation and induction of stress-response genes. We hypothesize that these effects are a result of the activation of an epigenetic check point that has evolved to protect the cell from undergoing replication in the absence of DNMT1. In chapter 3, we further explore the roles of DNMT1 in methylation independent regulation of gene expression, which has been suggested to in
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.85586 |
| Date | January 2004 |
| Creators | Milutinovic, Snezana |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Pharmacology and Therapeutics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002198799, proquestno: AAINR12911, Theses scanned by UMI/ProQuest. |
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