Grant: Operating Grant

A problem frequently encountered in cancer therapy is that of tumour cell resistance to therapeutic agents, so that although the majority of cells in a tumour will be destroyed, a small fraction will survive, and have the potential to metastasize. At present our ability to predict tumour response to treatment or diminish the resistance to radiation or drugs is very limited. Such methods are only likely to be developed when we have a clearer understanding, at the molecular level, of how cells respond to these agents. For many of these agents, DNA is considered to be the main target leading to cell death. It is known that cells have the capacity to repair much of this damage. Uncovering all the enzymes responsible for repair and learning how they operate is still a major task. This proposal focuses on a particular type of damage, DNA strand breaks, and on the role of a particular enzyme, polynucleotide kinase/phosphatase (PNKP), in mediating the repair of these lesions. We intend to learn how it interacts with other proteins required to mend strand breaks and if it plays an important role in making cells resistant to a variety of anti-cancer drugs. We also intend to develop inhibitors of this enzyme that may be used clinically to counter its activity in cancer cells and thereby improve the ability of the therapeutic agents to kill tumour cells.