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Chemical Mapping of G-Quadruplexes in the Genome

Reference	BB/G008337/1
Principal Investigator / Supervisor	Professor Sir Shankar Balasubramanian
Co-Investigators / Co-Supervisors
Institution	University of Cambridge
Department	Chemistry
Funding type	Research
Value (£)	316,935
Status	Completed
Type	Research Grant
Start date	21/05/2009
End date	20/11/2012
Duration	42 months

Abstract

Nucleic acid sequence motifs with four or more stretches of Gs are predisposed to the formation of four stranded structures called G-quadruplexes. Recent evidence suggests such motifs may exist throughout genomic DNA and that many such motifs are associated with cellular function(s). The evidence in support is largely based on in vitro biophysics and bioinformatics with some indirect evidence derived from functional studies. There is a need to directly address the central question in a cellular context. The proposed work aims to develop existing, validated small molecule G-quadruplex probes to specifically cross-link to G-qaudruplex structures in cells. Such probes will be employed to isolate G-quadruplex-containing DNA fragments from genomic DNA. The fragments will be sequenced using state-of-the-art massively parallel short read sequencing, and the sequences aligned against quadruplex sequence motifs we have computationally identified in the human genome. The principle outcomes of the study will be: a) to demonstrate that G-quadruplexes exist in the DNA of cells; b) to map out the binding sites of G-quadruplex binding ligands in cellular human genomic DNA.

Summary

The DNA found in living cells is the basis for programming the functions associated with life. It has been assumed that all DNA exists primarily as a canonical two stranded double helix, as proposed by Watson and Crick. However, there is mounting evidence to suggest that a four stranded quadruple helix DNA structure, called a quadruplex, may be able to form, and may have a functional significance. This proposal aims to directly explore whether such quadruplex structures exist in cell and to localise where in the ~ 3 Billion bases of DNA, in the human geneome, quadruplexes exist. The outcome(s) will directly address the central hypothesis and may also identify new functional targets for future therapeutics.

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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