Abstract
Cells in our bodies are frequently exposed to various stresses (e.g. UV, chemicals, infections, heat, starvation, osmotic and oxidative changes) that cause damages to essential molecules. Inefficiencies in cellular response mechanisms cause the damages to accumulate over time and contribute to age-associated diseases. Examples of such damages include the accumulation of toxic protein aggregates and unrepaired DNA damage that are commonly observed in neurodegenerative diseases.
Stress granules and DNA repair foci are evolutionarily conserved organelles whose defects in assembly and disassembly post-stress has been linked to defects in cell health. They concentrate certain proteins – including those that form toxic aggregates in neurodegenerative diseases – and RNAs without membrane enclosures. Dr. Lee’s postdoctoral work identified the mechanisms driving the formation of these organelles and demonstrated that their dynamic properties can change over time, leading to the formation of rigid protein aggregates found in disease. The Lee lab has been identifying cellular mechanisms that maintain the dynamic, functional states of stress-induced organelles including molecular chaperones, autophagy, microtubule-dependent transport using cutting-edge microscopy, protein biochemistry and biophysics, and human neurons derived from induced pluripotent stem cells. The Lee lab has also found that prolonged DNA damage response leads to the formation of persistent stress granules, linking the two stress response organelles. Small molecules that block the formation of stress granules improve health and function of neurons carrying disease-associated mutations, highlighting the potential of targeting these stress-responsive organelles for therapeutic benefit.
BioSketch
Dr. Hyun Ok (Kate) Lee is an assistant professor in the Department of Biochemistry at the University of Toronto. She received her B.Sc. in Molecular Biology at the University of Wisconsin – Madison, where her research focused on how stem cells contribute to the repair of damaged tissues. She received a Ph.D. in Genetics and Molecular Biology at the University of North Carolina at Chapel Hill, studying how cell growth, DNA replication, and damage are regulated during development and identifying new targets of Cullin4 E3 ubiquitin ligases. She completed her postdoctoral training in the laboratory of Dr. Tony Hyman at the Max Planck Institute of Molecular Cell Biology and Genetics where her work elucidated how groups of molecules assemble functional organelles without membrane enclosures. At the University of Toronto, her lab studies mechanisms that protect cells from stress-induced damages, focusing on understanding the regulation and function of stress-responsive organelles and their role in neurodegeneration.