Revealing DNA's Secret Structures with Ruthenium: From the Test Tube, to the Cell

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iThere is a lot more to DNA than the Watson-Crick double helix. As a flexible polymer, it folds in different ways adopting many different secondary structures.(i) Much less is known about these structures - how and when they form, what they do and how their structure relates to their role. Even so, such "alternative" structures have been linked to switch on/off of genes, and thus genetic diseases such as diabetes and cancer.This 3.5 year PhD studentship is funded by an EPSRC Doctoral Training Partnership and focuses on one such structure, the i-Motif (iM). Existence of iM in organisms was proven in 2018,(ii) but little is known about its biological structure/function relationships, and research is held back by a lack of effective detection methods that can be applied to live cells and organisms. However, we recently discovered a ruthenium complex that can, in vitro, detect iM in the presence of other DNA forms through a phosphorescence lifetime increase,(iii) and is likely compatible with living systems. The goal of this studentship is to improve our lead compound, increasing the strength and specificity of its response, improve our understanding of its phosphorescence switch on, and begin the work of translating this research from the test tube to cells. As such, the project, led by Dr John Fielden, is highly interdisciplinary. It will involve training in a wide range of techniques, from synthesis of new ligands and complexes, to characterisation of their interaction with DNA and their effect in cells, and involves both internal and external collaborations.