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RNA Quadruplexes that Regulate Gene Expression

Reference	BB/E019773/1
Principal Investigator / Supervisor	Professor Sir Shankar Balasubramanian
Co-Investigators / Co-Supervisors
Institution	University of Cambridge
Department	Chemistry
Funding type	Research
Value (£)	325,238
Status	Completed
Type	Research Grant
Start date	01/08/2007
End date	28/02/2011
Duration	43 months

Abstract

Nucleic acid sequence motifs with four or more stretches of Gs are predisposed to the formation of four stranded G-quadruplexes. Recent evidence points to the existence and function of such motifs in telomeres and also in gene promoters. We have very recently (unpublished) identified an RNA quadruplex in the 5'-UTR of the protooncogene N-Ras. Using biophysics and mutagenesis, we have demonstrated that this RNA quadruplex reduces the effciciency of translation. This proposal is based on our hypothesis that RNA quadruplexes in the 5'UTR of genes modulate the expression of genes at the translational level. In the proposed work we aim to elucidate this phonomenon using the N-Ras system as a paradigm. We will explore the consequence of where the quadruplex is located within the UTR and also the effect of altering its stability, by mutagenesis, by studying the translation efficiency using reporter gene constructs. We will also identify small molecule and protein ligands that bind and stabilise the N-Ras RNA quadruplex. These ligands will be employed in studies to demonstrate ligand induced translation modulation at the cellular level. We have identified some 3,000 human genomic transcripts that contain a RNA quadruplex motif within the 5'-UTR. Thus, the outcome of these experiments will provide insights that can be generalised to a large number of genes.

Summary

The DNA in living cells encodes for all genes. When a particular gene is switched on, the cell's machinery produces a transcript called RNA, and it is the RNA that directs the synthesis of proteins using the machinery of cells called ribosomes. We have identified short stretches of RNA that can form well defined, yet unusal quadruple helix folded structures called G-quadruplexes in many transcripts. We have recently found evidence to support that the formation of the quadruple helix in RNA can switch 'off' the gene by inhibiting the function of the ribosomes. This proposal aims to explore this recent finding and to also explore the possibility of generating molecules that can bind to quadruplexes in RNA and thus turn off the associated gene. This might in the longer term lead to a new class of therapeutic agents that function by selectively targeting RNA secondary structures rather than proteins.

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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