Award details

Quadruplex switching in DNA sequences

Reference	BB/C51444X/1
Principal Investigator / Supervisor	Professor Sir Shankar Balasubramanian
Co-Investigators / Co-Supervisors
Institution	University of Cambridge
Department	Chemistry
Funding type	Research
Value (£)	216,513
Status	Completed
Type	Research Grant
Start date	01/09/2005
End date	31/03/2009
Duration	43 months

Abstract

It has been know for some time that certain G-rich stretches of DNA or RNA have a propensity to fold into four-stranded structures called G-quadruplexes. Such structures have been implicated in mechanisms that have potential to regulate cell division, either by inhibiting the action of telomerase enzyme, or by disrupting the structure of the telomere. More recently, there is evidence emerging that suggests G-quadruplexes may form within double standard genomic DNA under certain conditions. Furthermore, there is proof of concept data in support of such quadruplexes playing a role in the regulation of a nearby gene. We are expanding this concept into a broader hypothesis that is currently under investigation. One of the critical aspects of the concept that needs investigating is factors that govern conformational switching between duplex and quadruplex forms of DNA. This proposal aims to carry out detailed biophysical investigations into the duplex-to-quadruplex switching mechanism. The methodology to be used is a FRET-based reporter system that will generate a significant change in fluorescence in going from one structural form to the other. Three quadruplex systems have been chosen from the genome for investigation, to establish thermodynamic and kinetic parameters that characterise each system in their native sequence context. As an extension of these studies, the influence of point mutations and quadruplex binding ligands on the conformational switching will be evaluated. These studies will provide insights into whether disease-related mutations may manifest via stabilisation or destabilisation of one of the two conformational states, and also whether ligands have the potential to promote quadruplex formation, which may open up possibilities for altering the regulation of specific genes as a way forward to generate a novel class of therapeutics. The further validate some of the data from the in-vitro studies, the fluorescence based system will also be adapted forstudies to be carried out in live cells.

Summary

unavailable

Committee	Closed Committee - Biomolecular Sciences (BMS)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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