Kingsbury, S.R.; (2006) Evaluation of the DNA replication licensing machinery as an anti-proliferative target. Doctoral thesis , University of London.

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Abstract

Cancer is the second leading cause of death in the developed world. However despite significant advances in chemotherapy during the latter half of the 20th Century, the impact on mortality has been modest. There is therefore a profound need for the identification of novel strategies to treat cancer. The DNA replication licensing pathway, which co-ordinates the decision to initiate DNA replication, has recently emerged as a potential anti-cancer target. The early dysregulation of the replication licensing machinery during tumourigenesis suggests that agents targeting this pathway may have high efficacy in tumour cells. However, the response of normal cells to such agents must also be considered. Here I show that withdrawal of cells from the mitotic cell cycle into the out-of-cycle states of quiescence and differentiation is tightly coupled to down-regulation of the DNA replication licensing machinery. Importantly, stem/progenitor cells of self- renewing tissues display an unlicensed replication phenotype. These results indicate that normal out-of-cycle functional, differentiated and stem/progenitor cell populations will be refractory to agents targeting the replication licensing machinery. Rapidly proliferating normal cell populations can suffer severe genotoxic and cytotoxic damage in response to chemotherapy. Here I show that inhibition of origin licensing in normal proliferating cells invokes the reversible activation of a putative origin licensing checkpoint which stalls cells in Gl until the block to origin licensing is removed, thereby protecting cells from damage. In contrast, transformed cells respond to inhibition of origin licensing by inducing apoptosis, suggesting that origin licensing inhibitors may represent highly specific cancer killing agents. Finally, I have utilised a cell-free DNA replication and chromatin-binding assay to analyse the biochemical properties of two potential lead compounds: the endogenous origin licensing repressor geminin and a viral pathogen HPV1 E4. Collectively, these studies reinforce the concept that the inhibition of DNA replication licensing represents a novel chemotherapeutic strategy to combat cancer.

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