Control of rDNA damage and the potentiation of cGAS-STING mediated immune signals

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This project is at the intersection of Multimorbidities and Prevention and early detection. Ageing increases the risk of cardiovascular disease, cancer, diabetes and neurodegeneration, which reduce quality of life and are life-limiting. Importantly, variation in severity and penetrance of these disorders across the population indicates that our biological age. This project seeks to unravel the mechanism of the strong links between the stability of rDNA repeats and biological ageing.Ageing associated conditions such cardiovascular disease, neurodegeneration, diabetes and cancer, vary in their severity and penetrance across the population indicating that chronological ageing is distinct from biological age, likely due to both genetics and environment. Genetic syndromes and lifestyle can influence cellular biological ageing through increased DNA damage or decreased DNA repair. Defective DDR signalling drives genomic instability primarily via increased replication stress at common fragile sites, telomeres and the ribosomal rDNA repeats (rDNA), which due to their repetitive nature are difficult to replicate. Thus, a reduced ability to regulate rDNA is likely to lead to increased genomic instability. In addition to being difficult to replicate, the rDNA repeats are sensitive to exogenous DNA damage with the progressive loss of damaged repeats being proposed as a mechanism to maintain genomic stability. Loss of rDNA repeats in response to DNA damage is associated with decreased cellular fitness and ageing. Lifestyle exposure to agents that increase DNA replication stress (environment) or an inability to repair endogenous DNA lesions (genetic/epigenetic) may preferentially induce a reduction in rDNA repeats, which may be linked to biological ageing via decreasing cellular and tissue fitness. In general, the association of DNA damage associated rDNA loss with longevity is well-described in yeast models and this proposal aims to address the hypothesis that this mechanism similarly plays a role in mammalian ageing and cancer.