Responses of Replication, Recombination and Checkpoint Signalling Pathways to Unrepaired PAH Adducts in DNA

Tobacco consumption has been clearly shown to increase an individual's risk for lung as well as other cancers, an concern of great importance for the economy and public health of the citizens of Kentucky. Specific components of tobacco smoke are carcinogens that damage DNA, the genetic material inside each cell. A significant amount of research has demonstrated that carcinogens in tobacco smoke are converted to intermediates that react with DNA in a particular way to distort its chemical structure. If this damage is not repaired by cells, these distortions cause problems during the replication of DNA that is required for cell division. Under some circumstances, the result of replication of damaged DNA is a permanent change (known as a mutation) in the information coded by the DNA within that cell. In the lung and other tissues, as mutations accumulate over time due to exposure to carcinogens, the probability increases that specific genetic changes will occur that cause cells to grow in the uncontrolled manner characteristic of human cancers. The high level of exposure of the lungs to carcinogens during smoking certainly explains the higher incidence of lung cancer among smokers than non-smokers. The distortions generated in DNA by tobacco carcinogens do not always cause mutations. DNA is so often damaged that cells have devised several ways to respond to damage in DNA to avoid mutations. Damage can be removed by processes known collectively as DNA repair that restore the correct structure of DNA and the information it encodes. If damage persists while DNA is being replicated, the distorted structure may actually block replication. It is now thought that the blockage of this replication process can be resolved in several different ways. One way is through an error-prone pathway that is the cause of mutations. Alternatively, replication blocks may be resolved by other means that appear to be error-free and thereby avoid mutations. In addition, cells may also respond by delaying their own division process or even by committing suicide, anti-cancer processes that minimize the persistence of cells with genetic damage. It is not known how the cell decides between error-free responses or mutation induction. The focus of this proposal is to determine what types of DNA damage caused by tobacco carcinogens block DNA replication and how this might be channeled into pathways that prevent or cause mutations. Since mutations are the root causes of cancer, the understanding of these processes will hopefully allow us to design strategies to prevent mutations and thus lower the incidence of lung cancer in the general population.