Understanding Genome Stability
Background: the identification of novel proteins involved in genome maintainance
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. The mechanisms involving a cell’s response to DNA damage include the direct repair of damage and modification of cell cycle progression, but they remain poorly understood. Interestingly, a cell’s response to DNA damage also involves damage tolerance, where the damage is essentially ignored until it may be repaired later, but commonly at the cost of induced mutation. Such induced mutations in the human genome could then lead to the onset of diseases, such as cancer, and thus, the identification and characterization of the genes involved could represent a 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 mechanisms of damage repair and tolerance. Using the collection of Saccharomyces cerevisiae deletion strains, we first performed a screen for genes involved in survival after DNA damage induced by treatment with ultraviolet (UV) light or the DNA methylation agent, methyl methanesulfonate. We then further characterized several genes identified from the screen, including