DNA instability plays an important role in the initiation and progression of cancer. Sequencing of DNA in cancer patients has identified many tumor-specific mutations that are not found in normal cells. These tumor-specific mutations were predominantly found in genes that function in DNA stability. To assess the role of these mutations and their impact on cancer initiation/progression, we will introduce the human genes that are mutated in cancer into a model organism to facilitate the systematic study of these tumor-specific mutations. In this study, the budding yeast is used as the model organism because the genes and proteins that are involved in cellular division and DNA stability are essentially the same between yeast and human cells. Further, genetic manipulations, genomic engineering, and high-throughput experiments are easier, quicker, and cheaper to carry out in the budding yeast. Once we introduce the human genes into yeast, we will insert the tumor-specific mutations into the genes and follow it with a synthetic-lethal screen. Synthetic lethality occurs when a mutation in either gene A or B has no effect on the cell, but mutations in genes A and B simultaneously cause the cell to die. The synthetic-lethal screen will allow us to examine on a genome-wide level whether there are secondary sites that when mutated will specifically be lethal with the mutated human gene and not the normal gene. The synthetic lethal interaction will then be confirmed in other model organisms and mammalian cells. These secondary sites would serve as potential anti-cancer targets thereby setting up the basis for the development of anti-cancer therapeutics that specifically target the killing of cancer cells and not normal cells in humans.