Grant: Project 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 carrying out the repair of these lesions. We intend to learn how PNKP interacts with other proteins required to mend strand breaks. Almost all cancer cells lack specific proteins called tumour suppressor proteins. We have found that cells that have lost specific proteins called tumour suppressors either die or become very weak if PNKP is also lost. This is a process called synthetic lethality and it presents an opportunity to target cancer cells rather than normal cells. In order to make full use of this opportunity we will investigate the mechanism(s) responsible for synthetic lethality involving loss of PNKP. We will also further investigate why reducing the level of PNKP stimulates the immune response. Finally, because we have evidence that backup proteins exist that can partially compensate for the loss of PNKP, we will seek to identify these proteins.