Grant: Discovery Grants Program - Individual

BACKGROUND: A stable genome is a fundamental property of all eukaryotes that is vital to the maintenance and accurate partitioning of DNA into daughter cells. Thus, genome stability is essential for normal cell function, physiology and species survival. Chromosome stability (CS), or the accurate maintenance of normal chromosome numbers and DNA content is vital for genome stability, yet a huge gap exists in our fundamental understanding of the genes, proteins and pathways (i.e., molecular determinants) that regulate CS. My NSERC Discovery program seeks to fill this gap by identifying and functionally characterizing the molecular determinants of CS, to gain unprecedented insight into normal cell function and physiology. VISION & APPROACH: My overarching and long-term vision is to expand our rudimentary understanding of the mechanisms required for CS in higher eukaryotes. My previous discovery grant (DG) developed novel, quantitative imaging microscopy (QuantIM) tools to rapidly identify and functionally evaluate CS genes and proteins. Bolstered by industrial partnerships that enhance my analytical capabilities and throughput, I am now applying these innovative tools to gain unparalleled insight into the molecular determinants of CS. My data now point to the potential importance of ubiquitin homeostasis as a key regulator of CS in higher eukaryotes. Ubiquitin is a small polypeptide found in all eukaryotes that can be covalently attached to target proteins to regulate function by affecting cellular localization, protein interactions and degradation. In humans there are 1024 genes that regulate ubiquitin homeostasis including 929 ubiquitination and 95 deubiquitination genes, that add and remove ubiquitin from targets, respectively. Using our CRISPR and QuantIM tools, my team will create novel models enabling us to define the underlying mechanisms required for CS. By employing biochemical, cell biology, genetic and proteomic tools, we will gain a detailed understanding of the fundamental roles ubiquitin homeostasis has in CS. IMPACT: Overall, my DG will yield important new knowledge that will greatly advance our fundamental understanding of CS and its impact on normal cell function and physiology in higher eukaryotes. Thus, my DG will impact and be of interest to geneticists and cell biologists but will also generate applied/translational interest as well. TRAINING: I have built a training ecosystem committed to removing systemic barriers and biases, recognizing the strength diversity has to offer and ensuring that all HQP are supported equally with each valued and respected for their contributions. I will train ~15 HQP over the next 5 years. HQP benefit from my productive and collaborative natural sciences and engineering environment, where they receive extensive technical and theoretical training to advance their specific projects, which will strategically position them for related training and future job prospects within academia and industry.