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.
Quadparser software can be accessed here.
References:
5′-UTR RNA G-quadruplexes: translation regulation and targeting
A Bugaut; S Balasubramanian
Nucleic Acids Research, 40 (11), 4727-4741 (2012)
DOI: 10.1093/nar/gks068
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Experimental Approaches to Identify Cellular G-quadruplex Structures and Functions
M D Antonio; R Rodriquez; S Balasubramanian
Methods, 57 (1), 84-92 (2012)
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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., 8 (3), 301-10 (2012)
DOI: 10.1038/nchembio.780
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FANCJ coordinates two pathways that maintain epigenetic stability at G-quadruplex DNA
P Sarkies; P Murat; L G Phillips; K J Patel; S Balasubramanian; J E Sale
Nucleic Acids Research, 40 (4), 1485-98 (2012)
DOI: 10.1093/nar/gkr882
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Demonstration of Ligand Decoration, and Ligand-Induced Perturbation, of G-Quadruplexes in a Plasmid Using Atomic Force Microscopy
I Mela; R Kranaster; R M Henderson; S Balasubramanian and J M Edwardson
Biochemistry, 51 (2), 578–585 (2012)
DOI: 10.1021/bi201600g
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Synthesis of Bis-indole Carboxamides as G-Quadruplex Stabilizing and Inducing Ligands
J Dash; R N Das; N Hegde; G D Pantoş; P Shirude; S Balasubramanian
Chem. European Journal, 18 (2), 554-64 (2012)
DOI: 10.1002/chem.201102556
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A single-molecule platform for investigation of interactions between G-quadruplexes and small-molecule ligands
D Koirala, S Dhakal, B Ashbridge, Y Sannohe, R Rodriguez, H Sugiyama, S Balasubramanian and H Mao
Nature Chemistry, 3, 782-787 (2011)
DOI: 10.1038/nchem.1126
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A Sequence-Independent Analysis of the Loop Length Dependence of Intramolecular RNA G-Quadruplex Stability and Topology
A Zhang, A Bugaut and S Balasubramanian
Biochemistry, 50, 7251-7258 (2011)
DOI: 10.1021/bi200805j
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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, 10, 261-275 (2011)
DOI:10.1038/nrd3428
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Rudimentary G-quadruplex-based telomere capping in Saccharomyces cerevisiae
J S Smith, Q Chen, L A Yatsunyk, J M Nicoludis, M S Garcia, R Kranaster, S Balasubramanian, D Monchaud, M Teulade-Fichou, L Abramowitz, D C Schultz and F B Johnson
Nature Structural & Molecular Biology, 18, 478-485 (2011)
DOI: 10.1038/nsmb.2033
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Synthesis and Binding Studies of Novel Diethynyl-pyridine Amides with Genomic Promoter DNA G-quadruplexes
J Dash, ZA E Waller, G D Pantos and S Balasubramanian
Chem. European Journal, 17, 4571-4581 (2011)
DOI: 10.1002/chem.201003157
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G-Quadruplex-Binding Benzo[a]phenoxazines Down-Regulate c-KIT Expression in Human Gastric Carcinoma Cells
K I E McLuckie, Z A E Waller, D A Sanders,D Alves,R Rodriguez, J Dash, G J McKenzie, A R Venkitaraman and S Balasubramanian
J. Am. Chem. Soc. 133,2658–2663 (2011)
DOI: 10.1021/ja109474c
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Small-molecule-mediated G-quadruplex isolation from human cells
S Muller, S Kumari, R Rodriguez and S Balasubramanian
Nature Chemistry, 2, 1095-1098 (2010)
DOI: 10.1038/NCHEM.842
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Targeting the c-Kit Promoter G-quadruplexes with 6-Substituted Indenoisoquinolines
M Bejugam, M Gunaratnam, S Mueller, D A Sanders, S Sewitz, J A Fletcher, S Neidle and S Balasubramanian
ACS Med. Chem. Lett. 1, 306–310 (2010)
DOI: 10.1021/ml100062z
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The BCL-2 50 Untranslated Region Contains an RNA G-Quadruplex-Forming Motif that Modulates Protein Expression
R Shahid, A Bugaut and S Balasubramanian
Biochemistry, 49, 8300–8306 (2010)
DOI: 10.1021/bi100957h
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Small Molecule-mediated inhibition of translation by targeting a native RNA G-quadruplex
A Bugaut, R Rodriguez, S-T D Hsu and S Balasubramanian
Org. Biomol. Chem., 8, 2771-2776 (2010)
DOI: 10.1039/c002418j
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Ensemble and single molecule FRET analysis of the structure and unfolding kinetics of the c-kit promoter quadruplexes
A Fegan, P S Shirude, L Ying and S Balasubramanian
Chem.Commun. 46,946-948 (2010)
DOI: 10.1039/b920680a
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Genome-wide analysis of a G-quadruplex-specific single-chain antibody that regulates gene expression
H Fernando, S Sewitz, J Darot, S Tavaré, J L Huppert and S Balasubramanian
Nucleic Acids Research, 37, 6716-6722 (2009)
DOI: 10.1093/nar/gkp740
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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., 131, 13399-409 (2009)
DOI: 10.1021/ja904007p
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G-quadruplex DNA bound by a synthetic ligand is highly dynamic
P V Jena, P S Shirude, B Okumus, K Laxmi-Reddy, F Godde, I Huc, S Balasubramanian and T Ha
J. Am. Chem. Soc., 131, 12522-3 (2009)
DOI: 10.1021/ja903408r
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A small molecule that disrupts G-quadruplex DNA structure and enhances gene expression
Z A Waller, S A Sewitz, S T Hsu and S Balasubramanian
J. Am. Chem. Soc., 131, 12628-33 (2009)
DOI: 10.1021/ja901892u
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G-quadruplex nucleic acids as therapeutic targets
S Balasubramanian and S Neidle
Current Opinion in Chemical Biology, 13, 345-353 (2009)
DOI: 10.1016/j.cbpa.2009.04.637
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Controlled-folding of a small molecule modulates DNA G-quadruplex recognition
S Muller, G Dan Pantos, R Rodriguez and S Balasubramanian
Chem.Commun., 80-82 (2009)
DOI: b816861.j
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Recognition and discrimination of DNA quadruplexes by acridine-peptide conjugates
J E Redman, J M Granadino-Roldán, J A Schouten, S Ladame, A P Reszka, S Neidle and S Balasubramanian
Org. Biomol. Chem., 7, 76-84 (2009)
DOI: b814682a
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FANCJ Is a Structure-specific DNA Helicase Associated with the Maintenance of Genomic G/C Tracts
T B C London, L J Barber, G Mosedale, G P Kelly, S Balasubramanian, I D Hickson, S J Boulton and K Hiom
J. Biol. Chem., 283, 36132-36139 (2008)
DOI: 10.1074/jbc.M808152200
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Position and Stability Are Determining Factors for Translation Repression by an RNA G-Quadruplex-Forming Sequence within the 5' UTR of the NRAS Proto-oncogene
S Kumari, A Bugaut and S Balasubramanian
Biochemistry, 47, 12664-12669 (2008)
DOI: 10.1038/nchembio864
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Diarylethynyl Amides That Recognize the Parallel Conformation of Genomic Promoter DNA G-Quadruplexes
J Dash, P S Shirude, S-T D Hsu and S Balasubramanian
J. Am. Chem. Soc., 130, 15950-15956 (2008)
DOI: 10.1021/ja8046552
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A Novel Small Molecule That Alters Shelterin Integrity and Triggers a DNA-Damage Response at Telomeres
R Rodriguez, S Muller, J A Yeoman, C Trentesaux, J-F Riou and S Balasubramanian
J. Am. Chem. Soc., 130, 15758-15759 (2008)
DOI: 10.1021/ja805615w
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G-quadruplexes: the beginning and end of UTRs
J L Huppert, A Bugaut, S Kumari and S Balasubramanian
Nucleic Acids Res., 36, 6260-6268 (2008)
DOI: 10.1093/nar/gkn511
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Selective Recognition of a DNA G-Quadruplex by an Engineered Antibody
H Fernando, R Rodriguez and S Balasubramanian
Biochemistry, 47, 9365-9371 (2008)
DOI: 10.1021/bi800983u
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Single molecule conformational analysis of DNA G-quadruplexes
P S Shirude and S Balasubramanian
Biochimie, 90, 1197-1206 (2008)
DOI: 10.1039/b801465e
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G-quadruplex recognition by bis-indole carboxamides
J Dash, P S Shirude and S Balasubramanian
Chem. Commun., 3055-3057 (2008)
DOI: 10.1039/b806042h
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Single molecule conformational analysis of the biologically relevant DNA G-quadruplex in the promoter of the proto-oncogene c-MYC
P S Shirude, L Ying and S Balasubramanian
Chem. Commun., 2007-2009 (2008)
DOI: 10.1039/b801465e
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Exploring the differential recognition of DNA G-quadruplex targets by small molecules using dynamic combinatorial chemistry
A Bugaut, K Jantos, J-L Wietor, R Rodriguez, J K M Sanders and S Balasubramanian
Angew. Chem. Int. Ed., 47, 2677-2680 (2008)
DOI: 10.1002/anie.200705589
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Triarylpyridines: a versatile small molecule scaffold for G-quadruplex recognition
Z Waller, P Shirude, R Rodriguez and S Balasubramanian
Chem. Commun., 1467-1469 (2008)
DOI: 10.1039/b718854d
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A Sequence-Independent Study of the Influence of Short Loop Lengths on the Stability and Topology of Intramolecular DNA G-Quadruplexes
A Bugaut and S Balasubramanian
Biochemistry, 47, 689-697 (2008)
DOI: 10.1021/bi701873c
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