Grant: Discovery Grants Program - Individual

The SOS response was first discovered in bacteria as a means of tolerating environmental radiation and genotoxic chemicals. No similar phenomenon has yet been observed in eukaryotes; however, genome-wide analyses have identified a large number of yeast genes whose expression increases in response to DNA damage. My laboratory aims to understand molecular mechanisms of transcriptional response to DNA damage using yeast as a model. Supported by NSERC, we found that several yeast genes are regulated by a common pathway with features reminiscent of the bacterial SOS system. However, unlike bacterial SOS, yeast cells appear to utilize ubiquitination and phosphorylation systems to modify target proteins involved in sensing DNA damage and relaying signals. We recently made a highly significant discovery regarding the signal transduction leading to transcriptional response and cell cycle control, and convincingly demonstrated a regulatory mechanism similar to the bacterial SOS response. It also becomes clear through our study that not all DNA damage inducible genes share the same promoter elements and that they probably belong to several distinct groups (regulons). Here we propose both genome-wide screens and detailed molecular analyses of selected genes aiming at understanding how several hundred genes are coordinately regulated in response to DNA damage at the transcriptional level. Elucidation of these signal transduction cascades has three important implications. First, it helps us to uncover fundamental biological processes of gene regulation and development, a key process of life. Second, DNA damage is the leading cause of human genetic diseases including cancer, and the vast majority (>90%) of chemical carcinogens are DNA damaging agents. We have utilized the above knowledge to develop a genotoxicity test capable of detecting and assessing environmental carcinogens. Finally, we have found that all the regulatory genes in this proposed study are highly conserved within eukaryotes, from yeast to human. Hence, our proposed studies can be applied to multicellular organisms, and contribute to agriculture, the environment and public health.