Research Summary

Innovative Nucleoside Probes as Multifunctional Toolbox to Study RNA Structure, Dynamics and Function

Understanding the structure-function relationship of G-quadruplex forming sequences in cells 

Genome-wide computational analysis has revealed the presence of several putative G-quadruplex (GQ) forming sequences in the telomeric repeats, promoter DNA regions and UTRs of mRNA. Biochemical and biophysical investigations suggest that such sequences may play critical roles in chromosome maintenance and regulation of proliferation-associated genes. In terms of structure, G-rich sequences adopt a variety of folding topologies in vitro, which depend on the sequence and ionic conditions. Although the formation of GQ structures in mammalian cells has been documented recently, it is not clear what topology a G-rich sequence adopts inside the cell and which structure is responsible for its function.

         In this context, moving away from the traditional approach of “one label-one technique”, we have employed an innovative approach to investigate the GQ structure and function in cell-free and cellular systems by using conformation-sensitive multifunctional nucleoside analogue probes.  We have developed novel minimally perturbing nucleoside analogues equipped with hybrid labels, which would enable the concurrent analysis of GQs in real-time and 3D by fluorescence, NMR and X-ray crystallography techniques. These studies would not only accelerate the discovery of new diagnostic tools and therapeutic strategies, but also would significantly advance our fundamental understanding of nucleic acid structure and function.

Figure Legend: Schematic diagram illustrating the investigation of structure-function relationship of nucleic acids using multifunctional nucleoside analogue probes.