Development of novel photochemical probes to investigate quadruplex DNA interactome in livings cells

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Genomic DNA is mainly folded into a double-stranded structure. However, guanine-rich regions can fold into alternative DNA structures called G-quadruplexes (G4), which have been recently visualized in human cells. G4s have been associated with genomic instability, regulation of gene expression and replication, and they are potential drug targets in a range of diseases. While the past decade has seen significant advances in the characterisation of G4 DNA structures, there remains a significant lack of understanding of the proteins responsible for G4-recongition in cells, which is key to further elucidate G4s' biological significance. This project aims to bridge this gap by developing photoactivatable probes that can label proteins bound to G4s in living cells. We recently demonstrated that Pt(II) complexes known to bind to G4s can also efficiently generate short-lived reactive oxygen species (ROS) under visible-light irradiation. We propose that these ROS can catalyse a known reaction between phenol-biotin reagents and proteins which will selectively biotinylate only proteins local to the G4, providing an enrichment handle for analysis by quantitative proteomics methods.