Understanding Genome Stability

Biological information is stored in the DNA sequences of an organism’s genome. Organisms go to extreme measures to protect the stability of the information, because DNA is a labile molecule that can undergo hydrolysis or modification within the cellular environment. However, at times a cell must modify the sequence of its genome by gene rearrangement or mutation; thus, pathways exist that control these processes as well. Such mutagenic pathways are especially interesting given the provocative hypothesis that, at times of excessive DNA damage, cells may hasten their own evolution by inducing mutation. Such induced mutations in the human genome could then lead to the onset of diseases, such as cancer. Thus, the identification of human genes involved in mutagenesis would be the critical first step in identifying protein targets whose inhibition with a small molecule could constitute a novel cancer prevention therapy.
	We have used budding yeast as a model eukaryote to study the origin of mutation in the genome. Using the collection of Saccharomyces cerevisiae deletion strains, we first performed a screen for genes involved in the repair of DNA damage induced by treatment with ultraviolet (UV) light or the DNA methylation agent, methyl methanesulfonate. From this initial screen we have characterized several genes, including WSS1, PSY2, PPH3, ESC4, and DOA1. These genes are currently under study. In addition, we have completed a screen for genes that when deleted render yeast unable to mutate and the characterization of these genes is also underway.