Grant: Project Grant

Cancer develops following 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 DNA damage. 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. In the present project, we will investigate the direct implication of the MYC oncogene in DNA repair. MYC is overexpressed in the majority of human cancers and has been extensively characterized as a protein that regulates gene expression. We believe that the activities of MYC in DNA repair are important for the survival and fitness of cancer cells. We will verify that the DNA repair activities of MYC explain why it cooperates with oncogenes that induce the production of free radicals and why it is overexpressed in cancers that aberrantly express an enzyme, activation-induced deaminase (AID) in Burkitt's lymphomas and APOBEC3B in multiple cancers, that modifies one of the normal bases of DNA. A potential outcome of this research will be the identification of a biochemical activity of MYC that could be inhibited with a drug.