Grant: Discovery Grants Program - Individual

All organisms are exposed to a variety of environmental stresses that pose a challenge to their survival. Stresses could include heat, cold, pollutants, radiation, oxygen radicals and chemicals in cigarette smoke, to name a few. These agents can elicit a variety of cellular stress responses that help cells deal with changes in cell physiology. Among the more renowned stress pathways is the p53 tumour suppressor pathway. The p53 protein is a transcription factor that is activated in response to many stresses, including most of those listed above. In general, transcription factors help control what genes are turned on or off at any given time. Activated p53 controls several genes that encode proteins involved in a form of cell death called apoptosis that helps eliminate highly damaged cells. However, over-reacting to cellular stresses could be detrimental by killing healthy cells, damaging healthy tissue. In fact, it is known that hyperactive versions of p53 accelerate aging in mouse models. Therefore, turning off the p53 transcription factor when its job is done is just as important as being able to turn it on. In recent years, my research program has been focussed on how the p53 response is shut off and controlled after a defined stress. We have found that the p53 response is designed to be able to turn on and off rapidly and that this involves the regulation of messenger RNAs (mRNAs) after they are made and is thus referred to as post-transcriptional regulation of gene expression. There are a variety of post-transcriptional regulatory steps that control the fate of mRNAs, including pre-mRNA splicing, alternative polyadenylation and microRNA-mediated gene silencing that all form a part of this proposal. In addition, we recently uncovered evidence that another well-known stress response is activated by a natural chemical from Ginkgo biloba leaves that interferes with the process of pre-mRNA splicing. Our work suggests that this stress pathway (the unfolded protein response) is initiated by the production of aberrant proteins and ultimately leads to the activation of three different transcription factors (XBP1, ATF3 and ATF6). We are proposing to decipher the link between pre-mRNA splicing defects and the unfolded protein response. In the present proposal, we will use a variety of technologies at the forefront of our field, including next generation sequencing, heterologous reporter constructs and CRISPR-mediated gene editing to address fundamental questions in gene regulation using the p53 response and the unfolded protein response to better understand the roles of post-transcriptional regulatory processes in maintaining homeostasis.