Involvement of the DNA-dependent protein kinase (DNA-PK) in p53-mediated apoptosis.

Throughout everyday life, our cells are exposed to many environmental factors (UV light, chemical carcinogens in the air, food or cigarettes) that could potentially cause them considerable harm, particularly to the cell's genetic material, DNA. If this DNA damage remains unchecked, it can be passed onto daughter cells (i.e., new cells produced after the division of the parent cell), eventually leading to the development of a cancer. To avoid this, the cell has a protein called p53 that acts as a cellular policeman. This protein tells the cell to immediately stop growing, allowing the cell time to repair this damage; or, should the damage be too severe, commit suicide by triggering a cellular process called apoptosis. In either event, the damaged DNA would not be passed onto daughter cells. The important questions remain: how is the damage sensed by p53 and how does it choose between cell growth arrest and apoptosis? It turns out that p53 does not sense the damage itself. Rather, damaged DNA is sensed by other proteins which then relay the message to p53 either directly, or via messengers. The identity of the sensor(s) and/or messenger(s) is crucial to our understanding of cancer development and predisposition, and the design of anti-cancer strategies. Previously, we identified one such messenger as a large protein called DNA-PK. We have since carried out a range of studies to support this claim. We demonstrated that when the cell has sustained severe DNA damage (damage beyond repair), DNA-PK and p53 quickly become closely associated, and communicate with each other. Specifically, DNA-PK informs p53 to carry out the suicidal process. The proposed research focuses on the precise mechanisms whereby DNA-PK executes this command, thereby preventing cancer development.