Disrupting DNA G-quadruplex secondary structures to revert premature ageing

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The underlying cause of aging remains one of the central mysteries of biology. Recent studies in several different biological models suggest that not only can the rate of aging be modified by environmental and genetic factors, but also that the aging clock can be reversed, restoring characteristics of youthfulness to aged cells and tissues.DNA packaging and organisation in the cell nucleus has been shown to be significantly altered thorough ageing and some accelerating ageing disorders. Treatment with small molecule ligands can interfere with nuclear organisation and revert premature ageing sings in patient-derived cells. DNA non-canonical structures, in particular DNA G-quadruplex structures, have also shown to play a role in DNA packaging in some accelerating ageing syndromes. Indeed, mutation of specific G-quadruplex unwinding proteins and accumulation of these DNA structures have been shown to be the underlying cause of accelerating ageing syndromes, such as Cockayne syndromes. Targeting DNA and its structural feature to both further our understating in fundamental ageing biology and explore potential for therapeutic intervention of rare accelerating ageing disorders, is an unexplored opportunity that needs to be investigated.Here, I will exploit a range of chemical biology tools to both investigate the fundamental role of DNA G-quadruplex structures in ageing biology, and explore the potential for therapeutic intervention of rare accelerating ageing syndromes by developing small molecules to target and disrupt these structures. Specifically, I will combine my experience with DNA G-quadruplex targeting and genome-wide mapping with a G-quadruplex selective live-cell imaging methodology that has been developed at the chemistry department of Imperial College London in collaboration with Dr. Vilar. I intend to address these specific questions:1) What are the global changes in G-quadruplex prevalence genome-wide in accelerating ageing disorders and how is DNA packaging affected by their formation? 2) Can targeting and disrupting the G-quadruplexes that accumulate via ageing be used to revert the ageing phenotypes by restoring correct DNA packaging?3) What are the dynamics in living cells, with respect to transcription and replication of DNA, that cause G-quadruplex formation thorough ageing?Addressing these questions will further our understanding of the cause and effect relationship between DNA secondary structure formation and gene mis-regulation that cause ageing. This will pave the way towards the development of novel therapeutic agents which will ultimately increase health-span and treat rare accelerating ageing syndromes.