Our research will aim to establish the role of DNA Helicases (WRN and BLM) as positive regulators of proteostasis and understand their impact of declining function prior to the onset of age-related proteostasis. Furthermore, the project will aim to develop genetic and pharmacological tools to modify DNA helicase activity, that may form the basis of intellectual property and therapeutics.
The ability to generate and maintain an optimal proteome is of paramount importance for long-term health. As such, cells have evolved a highly conserved network of protein quality control pathways, commonly referred to as the Protein homeostasis (Proteostasis) Network (PN), that operates across cells to neutralize the threat of misfolded, mislocalized and aggregated proteins throughout life. Despite this, the accumulation and persistence of aberrant protein species (known as a loss of proteostasis) is a common feature of aging in worms, flies, mice and humans, and is associated with the dysfunction of multiple tissues in aged individuals. These observations raise the possibility that maintaining proteostasis throughout life may be a powerful way to promote healthy aging; however, the cause of age-related proteostasis collapse remains poorly understood. A comprehensive interrogation of the relationship between PN activity, proteostasis capacity and aging in Caenorhabditis elegans, has revealed that the capacity of the PN declines in early adulthood due to the transcriptional repression of multiple PN components. Recently, the Di Antonio and Labbadia groups (of this proposal) have discovered that the DNA helicases, WRN-1/WRN and HIM-6/BLM, are required for the maintenance of proteostasis capacity in adulthood, suggesting that genome integrity early in life is intimately coupled with the propensity for proteostasis collapse with age.
In this project the investigators will explore the hypothesis that WRN-1 and HIM-6 activity positively regulate proteostasis capacity by preventing the inappropriate persistence of DNA G-quadruplex (G4) structures at the promoters of PN genes, and that the loss of DNA helicase activity and G4 homeostasis early in life underlies the repression of PN genes and proteostasis collapse with age. This will re-shape our understanding of the origins of age-related proteostasis collapse and highlight new mechanisms and pathways that can be targeted to preserve proteome integrity and prolong healthy tissue function. The project provides an opportunity to contribute to developing novel science around the role of G4 structures in healthy and unhealthy aging. Particularly of unique interest is the probing of both the wanted and unwanted G4 structures and their impact on proteostasis maintenance, which may create the opportunity for novel drug targets. The project specifically highlights the intent to produce a library of ligands and biological tools (possibly CRISPR, mRNA etc.) to perturb G4 structures which could form the basis of intellectual property around mechanism of action and molecular entities. The research plan incudes the production of G4 stabilizing and disrupting tools (ligands etc.) and measuring the impact of these within physiological conditions across multiple organisms including C. elegans and human cell lines. Commercial Viability - Opportunity to identify novel therapeutic targets relevant to longevity research, based on a molecular scaffold already identified by the investigators - Opportunity to contribute novel research to the field on the role of DNA helicases and G4 structures related to age related diseases