Grant: Operating Grant

Maintaining DNA integrity is essential to all forms of life and prevention of cancer. Despite its importance, it is continually damaged by exposure to many types of harmful agents. Estimates put the frequency of DNA damage at up to one million events each day in every cell. Although DNA is damaged in many ways, the most severe form occurs when DNA is broken into two or more pieces. If not repaired, cells harboring this kind of damage will die. If repaired improperly, genetic information will be altered, rendering such cells susceptible to misregulation events leading to the onset of cancer. Fortunately, cells have a number of proteins that collectively act as guardians of the genome. Although several of these guardian proteins have now been identified in humans the way in which they come together to form a functional DNA repair machine is not well understood. Using methods (such as X-ray crystallography) that permit the detailed three-dimensional visualization of proteins, our lab is approaching the understanding of DNA repair machinery from the perspective of a molecular mechanic. Our research is aimed at understanding specific parts of the 'machine' (ie. proteins) and their relationship to other parts of the machine. By achieving a better understanding of how the DNA repair machinery functions normally, our proposed research will inform why a person's DNA repair machinery malfunctions during the development of cancer and ultimately allow measures to be taken to either 'fix' the repair machinery before cancer causing mutations occur, or exploit this knowledge to develop more effective chemotherapeutic drugs useful in the treatment of individual cancers.