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Sequence occurrence and structural uniqueness of a G-quadruplex in the human c-kit promoter.

Todd, AK; Haider, SM; Parkinson, GN; Neidle, S; (2007) Sequence occurrence and structural uniqueness of a G-quadruplex in the human c-kit promoter. Nucleic Acids Res , 35 (17) 5799 - 5808. 10.1093/nar/gkm609. Green open access

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Abstract

The 22-nt c-kit87 promoter sequence is unique within the human genome. Its fold and tertiary structure have recently been determined by NMR methods [Phan,A.T., Kuryavyi,V., Burge,S., Neidle,S. and Patel,D.J. (2007) Structure of an unprecedented G-quadruplex scaffold in the c-kit promoter. J. Am. Chem. Soc., 129, 4386-4392], and does not have precedent among known DNA quadruplexes. We show here using bioinformatics and molecular dynamics simulations methods that (i) none of the closely related sequences (encompassing all nucleotides not involved in the maintenance of structural integrity) occur immediately upstream (<100 nt) of a transcription start site, and (ii) that all of these sequences correspond to the same stable tertiary structure. It is concluded that the c-kit87 tertiary structure may also be formed in a very small number of other loci in the human genome, but the likelihood of these playing a significant role in the expression of particular genes is very low. The c-kit87 quadruplex thus fulfils a fundamental criterion of a 'good' drug target, in that it possesses distinctive three-dimensional structural features that are only present in at most a handful of other genes.

Type: Article
Title: Sequence occurrence and structural uniqueness of a G-quadruplex in the human c-kit promoter.
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/nar/gkm609
Publisher version: http://dx.doi.org/10.1093/nar/gkm609
Language: English
Additional information: PMCID: PMC2034477. © 2007 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Base Sequence, Circular Dichroism, Computational Biology, Computer Simulation, DNA, G-Quadruplexes, Genomics, Humans, Models, Molecular, Promoter Regions, Genetic, Proto-Oncogene Proteins c-kit
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > SoP Pharmaceutical and Bio Chemistry
URI: http://discovery.ucl.ac.uk/id/eprint/1335478
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