Grant: Project Grant

Cancer develops following increased alterations within DNA, which are usually repaired by complex groups of proteins involved in DNA repair. Defects in one or more DNA repair mechanisms cause the accumulation of changes in DNA, called mutations, that increase the possibility that certain cells become tumorigenic. Paradoxically, once cancer cells emerge they are acutely dependent on certain DNA repair mechanisms, even more so than normal cells, because they proliferate rapidly and their metabolism generates highly reactive DNA-damaging molecules. Hence, to survive cancer cells must adapt by increasing their capacity to repair specific types of DNA damage. As a by-product of this adaptation, cancer cells become more resistant to therapies that cause DNA damage, such as chemotherapy and radiation. We have discovered one strategy that cancer cells use to augment their DNA repair capability. They can increase the expression of proteins that stimulate the activity of DNA repair enzymes. In contrast to DNA repair enzymes, these accessory proteins are not essential to normal cells under physiological conditions, but are required by cancer cells. This provides a therapeutic window to develop new drugs targeting accessory proteins to which cancer cells have become addicted to. Our characterization of the CUT domain family of proteins has established a paradigm in this field. We now have identified a novel accessory factor that stimulates a different DNA repair enzyme. In the current project, we will characterize the activity of this accessory protein, determine which cancers are dependent on it and demonstrate why cancer cells die without it whereas normal cells can survive. We will develop biochemical tests that are amenable to high-throughput screening in order to identify small molecules that inhibit the accessory protein. These studies are expected to target multiple cancers and eventually to provide new mechanisms to treat cancer.