G-quadruplex nucleic acids

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Nucleic acids are highly flexible molecules than can adopt different conformational structures. While in living systems DNA is largely double helical and RNA is single stranded, guanine-rich sequences can exist in alternative structural forms known as G-quadruplex nucleic acids. We are investigating the functional relevance of a quadruple helical form of nucleic acids and its implication for the biology of nucleic acids. The G-quadruplex hypothesis is of fundamental importance to life and may well hold the key to new therapeutic approaches in numerous areas of human disease that include cancer.

Specific mechanisms under investigation include: DNA G-quadruplex formation at the telomeres and their importance for genomic stability and replication; DNA G-quadruplexes in gene promoters and the regulation of transcription; RNA G-quadruplexes in the untranslated regions of mRNA and the control of protein synthesis (translation).

As part of our studies, we are synthesising new molecules that stabilise the nucleic acid quadruple helix and interfere with specific cellular processes. We make extensive use of biophysical methods (NMR, UV, CD and fluorescence spectroscopy) to study quadruplexes and their interactions with molecules. We are also employing computational methods (bioinformatics) and genomics to explore quadruplexes in genomes.

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Key Papers:

G-quadruplexes regulate Epstein-Barr virus–encoded nuclear antigen 1 mRNA translation
P Murat; J Zhong; L Lekieffre; N P Cowieson; J L Clancy; T Preiss; S Balasubramanian; R Khanna; J Tellam
Nature Chemical Biology, 201410, 358–364
DOI:10.1038/nchembio.1479
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Visualization and selective chemical targeting of RNA G-quadruplex structures in the cytoplasm of human cells
G Biffi; M Di Antonio; D Tannahill; S Balasubramanian
Nature Chemistry, 2014, 6, 75
DOI: 10.1038/nchem.1805
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Existence and consequences of G-quadruplex structures in DNA
P Murat; S Balasubramanian
Current Opinion in Genetics and Development, 2014, 25, 22-29
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Quantitative visualization of DNA G-quadruplex structures in human cells
G Biffi; D Tannahill; J McCafferty; S Balasubramanian
Nature Chemistry, 2013, 5, 182-186
DOI: 10.1038/nchem.1548
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Selective RNA Versus DNA G-Quadruplex Targeting by In Situ Click Chemistry
M Di Antonio; G Biffi; A Mariani; E Raiber; R Rodriguez; S Balasubramanian
Angew. Chem. Int. Ed, 2012, 51 (44), 11073-11078
DOI: 10.1002/anie.201206281
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5′-UTR RNA G-quadruplexes: translation regulation and targeting
A Bugaut; S Balasubramanian
Nucleic Acids Research, 2012, 40 (11), 4727-4741
DOI: 10.1093/nar/gks068
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Small-molecule–induced DNA damage identifies alternative DNA structures in human genes
R Rodriguez; K M Miller; J V Forment; C R Bradshaw; M Nikan; S Britton; T Oelschlaegel; B Xhemalce; S Balasubramanian; S P Jackson
Nat. Chem. Biol., 2012, 8 (3), 301-10
DOI: 10.1038/nchembio.780
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Targeting G‐quadruplexes in gene promoters: a novel anticancer strategy?
S Balasubramanian, L H Hurley and S Neidle
Nature Reviews Drug Discovery, 2011, 10, 261-275
DOI:10.1038/nrd3428
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A G-Rich Sequence within the c-kit Oncogene Promoter Forms a Parallel G-Quadruplex Having Asymmetric G-Tetrad Dynamics
S T Hsu, P Varnai, A Bugaut, A P Reszka, S Neidle and S Balasubramanian
J. Am. Chem. Soc., 2009, 131, 13399-409
DOI: 10.1021/ja904007p
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G-quadruplex nucleic acids as therapeutic targets
S Balasubramanian and S Neidle
Current Opinion in Chemical Biology, 2009, 13, 345-353
DOI: 10.1016/j.cbpa.2009.04.637
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An RNA G-quadruplex in the 5' UTR of the NRAS proto-oncogene modulates translation
S Kumari; A Bugaut; J L Huppert; S Balasubramanian
Nature Chem. Biol., 2007, 3, 218-221
DOI: 10.1038/nchembio864
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Prevalence of quadruplexes in the human genome
J L Huppert; S Balasubramanian
Nucleic Acids Res., 200533, 2908-2916