Xu, Bowen; (2024) RNA polymerase III and ageing in the fruit fly Drosophila melanogaster. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Ageing is one of the core biological issues that urgently requires research and solutions, especially in our increasingly ageing society. Recent studies have begun to reveal the significant role of RNA polymerase III (Pol III)—a highly evolutionarily conserved component of all eukaryotic cells with fundamental biological functions—in the mechanisms of ageing. Pol III is responsible for transcribing small RNA molecules, including tRNA and 5S rRNA, which play crucial roles in protein synthesis and various cellular functions. However, much remains unknown about the detailed roles of Pol III in ageing. In this study, I first demonstrated that the FDA-approved anti-cancer drug trametinib, an inhibitor of MEK in the Ras/ERK pathway, can reduce Pol III activity in Drosophila. Trametinib extends the lifespan of Drosophila by inhibiting Pol III activity specifically in intestinal stem cells, with the Pol III inhibitor MAF1 playing a key role in this process. Conversely, I also showed that systemic loss of Maf1 can extend Drosophila lifespan, with this effect being specific to neurons, thereby enhancing healthspan. Furthermore, I demonstrated that the loss of Maf1 extends lifespan by promoting the expression of Pol III transcript 5S rRNA, counteracting the age-related decline of 5S rRNA in the brain. Lastly, I showed that the loss of Maf1 increases protein translation levels in neurons, likely through ribosome upregulation, alleviating the age-associated decline in neuronal protein translation and thereby extending lifespan. In a Drosophila neurodegenerative disease model with C9Orf72 repeats, characterized by toxic protein translation deficits, loss of Maf1 also improved survival rates. Overall, my research elucidates the paradoxical role of Pol III in ageing biology: both increased and decreased activity can extend lifespan, depending on the cell type. This suggests opposing ageing mechanisms for Pol III in stem cells and neurons. These findings provide valuable insights into human ageing and offer new perspectives and targets for developing more precise anti-ageing interventions.

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