Grant: CIHR Fellowship

Ribosomes are essential for life because they are the cellular factories for protein production. Defects in ribosomes cause ribosomapathies where patients exhibit bone marrow failure, developmental abnormalities, and increased cancer rates. The cell generates 7500 ribosomes per minute in mammals. To achieve this high-demand, the cell requires over 200 assembly factors and over 50% of its energy resources for ribosome biogenesis. The last 60 years of research has revealed the composition and structure of the ribosome, but the regulation for its assembly is still unclear. Las1 is an essential ribosome assembly factor; yet, we do not understand what role Las1 plays in ribosome production. Las1 has been shown to interact with two other proteins, Grc3 and the IPI complex, which are also crucial for ribosome assembly. Together, defects in Las1, Grc3, and the IPI complex have been associated with congenital lethal motor neuron disease, X-linked intellectual disability, prostate cancer, and breast cancer. The specific aims of my research is to identify the roles of Las1, Grc3, and the IPI complex in ribosome assembly and understand how environmental stress, such as heat shock, acidosis, and hypoxia, derail the assembly pathway. Targeting abnormal ribosome assembly for anti-cancer therapeutics is a growing field; however, this strategy has only recently come to fruition with a new drug, CX-5461, that is currently undergoing human clinical trials. Consequently, it is paramount to understand the regulation of ribosome assembly so that we may tap into this novel anti-cancer strategy. The long range goal of this work will be the development anti-cancer therapeutics targeting prevalent cancers such as prostate and breast cancers which impacts 1 in 8 Canadian males and 1 in 9 Canadian females, respectively.