Characterizing the evolutionarily conserved functions of the pre-mRNA processing factor 4 kinase in cellular stress

Only the most important cellular functions and genes are evolutionarily conserved between single cell organisms like amoebae and multi-cellular animals like humans. The pre-mRNA processing factor 4 kinase (PRP4K) is a gene that is highly conserved and found in many organisms from amoebae to humans. Early studies of the PRP4K gene demonstrated that it was essential in yeast cells and during worm development. PRP4K is essential for development as it was found to be a component of a protein complex involved in splicing of messenger RNA (mRNA), a process that enables one gene to produce several transcripts encoding different proteins. Despite being also an essential protein in human cells, work from the Dellaire laboratory and others has demonstrated that partial loss of PRP4K expression is common in breast and ovarian cancer, and leads to cellular changes that make these cancers more aggressive and therapy resistant. Chemotherapy causes great cellular stress, and similarly when tumours grow, they are subjected to cellular stresses including oxidative damage and nutrient deprivation. We hypothesize that loss of PRP4K alters how cancer cells respond to these stresses. Working with co-applicant Dr. Robert Huber (Trent University), an expert in the social amoeba Dictyostelium discoideum, this proposal will explore the fundamental role of PRP4K in regulating cellular stress responses that is conserved across 650 million years of evolution between amoebae and humans.