Establishing the importance of DNA helicases and G-quadruplex homeostasis for the maintenance of proteome integrity with age

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The accumulation of aberrant protein species (proteostasis collapse) is a conserved driver of age-related tissue dysfunction that emerges from transcriptional remodelling of the Proteostasis Network (PN) during early adulthood. At present, the underlying basis for changes in the expression of PN genes and the loss of proteostasis capacity with age, remain poorly understood, thereby hampering attempts to promote healthy tissue function in aged individuals. Recently, we have discovered that the expression of two DNA helicases, wrn-1/WRN and him-6/BLM, declines prior to the onset of proteostasis collapse, and that this correlates with the formation of DNA G-quadruplex (G4) structures and transcriptional repression at PN genes. Furthermore, we find that reducing WRN-1 or HIM-6 activity through RNAi, accelerates the transcriptional repression of PN genes and the loss of proteostasis capacity during adulthood. These observations strongly suggest that reduced WRN-1/HIM-6 activity and loss of G4 homeostasis early in life promotes transcriptional remodelling of the PN and leaves cells vulnerable to age-related proteostasis collapse. Here, we will use a multi-disciplinary approach to explore this possibility. We will establish precisely how reduced WRN-1/HIM-6 activity and increased G4 stability impact proteostasis capacity in different tissues with age and use genetic and chemical approaches to maintain DNA helicase activity and suppress G4 stabilisation in adulthood, thereby protecting the ageing proteome and prolonging healthy tissue function. This work will re-shape our understanding of the origins of age-related proteostasis collapse and act as a precursor for future work aimed at designing small molecules that can discretely maintain the expression of key PN genes in aged cells, thereby preserving proteome integrity and prolonging healthy tissue function with age.