Putative DNA Quadruplex Formation within the Human <i>c-kit</i> Oncogene

Rankin, Sarah; Reszka, Anthony P.; Huppert, Julian; Zloh, Mire; Parkinson, Gary N.; Todd, Alan K.; Ladame, Sylvain; Balasubramanian, Shankar; Neidle, Stephen

doi:10.1021/ja050823u

Cited by 529 publications

(476 citation statements)

References 46 publications

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“…This structural asymmetry determines the possibility of the formation of the two very closely related but distinct hybrid-1 and hybrid-2 structures. Unlike the G-rich sequences in gene promoter regions [57,58,[60][61][62][63][64][65][66][67], the telomeric DNA sequence is unique in that it contains the same tandem repeats with the same linker segments. Thus, in a telomeric sequence, any four-G-tract region has the same potential of forming an intramolecular G-quadruplex structure.…”

Section: Structure Polymorphism Of Human Telomeric G-quadruplexes Maymentioning

confidence: 99%

Polymorphism of human telomeric quadruplex structures

2008

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Human telomeric DNA consists of tandem repeats of the sequence d(TTAGGG). Compounds that can stabilize the intramolecular DNA G-quadruplexes formed in the human telomeric sequence have been shown to inhibit the activity of telomerase and telomere maintenance, thus the telomeric DNA G-quadruplex has been considered as an attractive target for cancer therapeutic intervention. Knowledge of intramolecular human telomeric G-quadruplex structure(s) formed under physiological conditions is important for structure-based rational drug design and thus has been the subject of intense investigation. This review will give an overview of recent progress on the intramolecular human telomeric G-quadruplex structures formed in K + solution. It will also give insight into the structure polymorphism of human telomeric sequences and its implications for drug targeting.

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Section: Structure Polymorphism Of Human Telomeric G-quadruplexes Maymentioning

confidence: 99%

Polymorphism of human telomeric quadruplex structures

2008

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“…[30][31][32] We have included three native G-quadruplex-forming sequences in this study: the human telomeric DNA quadruplex sequence H-telo 5 0 -GGG(TTAGGG) 3 -3 0 , the two c-Kit promoter G-quadruplex sequences of c-Kit 2 17 5 0 -GGG CGG GCG CGA GGG AGG GG-3 0 and c-Kit 1 15 5 0 -GGG AGG GCG CTG GGA GGA GGG-3 0 , all of which are dual labeled (5 0 -FAM and 3 0 -TAMRA). We also included a dual-labeled duplex DNA as a control (see the Experimental Procedures).…”

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confidence: 99%

Targeting the c-Kit Promoter G-quadruplexes with 6-Substituted Indenoisoquinolines

Bejugam

Gunaratnam

Müller

et al. 2010

ACS Med. Chem. Lett.

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Herein, we demonstrate the design, synthesis, biophysical properties, and preliminary biological evaluation of 6-substituted indenoisoquinolines as a new class of G-quadruplex stabilizing small molecule ligands. We have synthesized 6-substituted indenoisoquinolines 1a-e in two steps from commercially available starting materials with excellent yields. The G-quadruplex stabilization potential of indenoisoquinolines 1a-e was evaluated by fluorescence resonance energy transfer-melting analysis, which showed that indenoisoquinolines show a high level of stabilization of various G-quadruplex DNA structures. Indenoisoquinolines demonstrated potent inhibition of cell growth in the GIST882 patient-derived gastrointestinal stromal tumor cell line, accompanied by inhibition of both c-Kit transcription and KIT oncoprotein levels.KEYWORDS DNA, quadruplex, c-kit regulation, inhibition, ligand G -quadruplexes constitute a structural form of DNA that is distinct from the double helix. 1 They are formed from particular guanine-rich nucleic acid sequences in which guanines form planar quartets stabilized using the Watson-Crick and Hoogsteen edges to form hydrogen bonds. Their occurrence has been demonstrated within ciliate telomeres. 2,3 In addition, G-quadruplex sequence motifs (G 3þ N 1-7 G 3þ N 1-7 G 3þ N 1-7 G 3þ ) are found at many positions within genomes, 4,5 with a notable increase in density in close vicinity to transcriptional start sites, highly suggestive of a biological function in gene regulation. 5,6 NMR spectroscopy and X-ray crystallographical studies have shown that these guanine-rich sequences can fold into G-quadruplex structures in vitro. 7,8 Their unique structural features and possible biological functions make them attractive targets for drug design. 9,10 Genomic locations that are known to possess quadruplex structures include the immunoglobulin switch region and the promoters of numerous proto-oncogenes, such as c-MYC, 11 VEGF, 12 BCL-2, 13 and K-RAS. 14 Two quadruplex-forming motifs have been identified in the c-Kit promoter (c-Kit 1 15,16 and c-Kit 2 17,18 ). Here, we present a new class of quadruplex stabilizing compounds that have been used to explore relationships between quadruplexes and their biological functions.c-Kit is a proto-oncogene that codes for a 145-160 kDa protein belonging to the receptor tyrosine kinase (RTK) family. The KIT protein regulates signal transduction cascades that control cell growth and differentiation. 19 c-Kit expression has been shown to control the growth of various cell lines, including gastrointestinal stromal tumors (GIST), hematopoietic cells, small cell lung cancer, and colorectal cancer. [20][21][22][23] Gain-of-function mutations in the KIT protein are found in various highly malignant human cancers, especially GIST. Gleevec (imatinib mesylate), a small molecule antagonist originally developed to treat chronic myelogenous leukemia (CML), acts by maintaining the bcr-abl kinase in an inactive conformation. Gleevec is also the mainstay of target therapy ...

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“…Both sequences are 31 nucleotides apart from each other and were shown to form Gquadruplex structures in vitro. [21][22] As a model system we have chosen to study in detail the interaction between hPARP-1 and the quadruplex from the c-kit promoter which proved the most stable (c-kit-1). …”

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confidence: 99%

First Evidence of a Functional Interaction between DNA Quadruplexes and Poly(ADP-ribose) Polymerase-1

et al. 2008

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Abstract:We discovered that the abundant human nuclear protein poly(ADP-ribose) polymerase (hPARP-1) binds to intramolecular DNA quadruplexes in vitro with high affinity and with a stoichiometry of two proteins for one quadruplex. Using an enzymatic assay, we have shown that hPARP-1 gets catalytically activated upon binding to G-quadruplexes localized at the c-kit promoter and human telomere regions. This is the first example of a truly functional quadruplex-protein interaction which has possible implications in understanding hPARP-1 mediated mechanisms of transcription regulation and telomere end protection. 2It has been known for several decades that DNA sequences containing a high density of contiguous guanines grouped as clusters are able to adopt four-stranded secondary structures named guanine (G)-quadruplexes or tetraplexes. 1Converging in silico and in vitro data have recently revealed high prevalence of such G rich DNA sequences throughout the human genome. 2-4The identification of prokaryotic and eukaryotic proteins that interact with these motifs also reinforces the hypothesis that quadruplexes do form in vivo and that their formation is biologically relevant. and more recently regulation of gene transcription, [10][11][12] there is noticeable absence of examples for DNA quadruplex induced modulation of nuclear protein(s) function. When exploring protein-quadruplex interactions, attention has been almost exclusively focused on the effects of the natural DNA binding protein on the quadruplex structure and proteins have been classified according to their ability to stabilise, destabilise or promote the formation of DNA quadruplexes. 6-7Unnatural Cys 2 His 2 zinc finger proteins have also been engineered that bind to quadruplex DNA with high affinity [13][14] and block the biochemical functions of DNA polymerase and telomerase via quadruplex stabilization. , the exact role quadruplexes may play remains unknown.Herein, we discovered that the abundant human nuclear protein poly(ADP-ribose) polymerase (hPARP-1) binds to intramolecular DNA quadruplexes in vitro with high affinity and gets catalytically activated upon binding to G-quadruplexes. This is the first example of a truly functional quadruplex-protein interaction which has possible implications in understanding hPARP-1 mediated mechanisms of transcription regulation and telomere end protection.Our first goal was to demonstrate the interaction between hPARP-1 and an intramolecular promoter DNA quadruplex. Two G-rich sequences have been identified within the nuclease hypersensitive region of the human proto-oncogene c-kit that encodes for a tyrosine kinase receptor. Both sequences are 31 nucleotides apart from each other and were shown to form Gquadruplex structures in vitro. [21][22] As a model system we have chosen to study in detail the interaction between hPARP-1 and the quadruplex from the c-kit promoter which proved the most stable (c-kit-1). 21However we also investigated the interaction with other intramolecular quadruplexes, including the seco...

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Putative DNA Quadruplex Formation within the Human c-kit Oncogene

Cited by 529 publications

References 46 publications

Polymorphism of human telomeric quadruplex structures

Polymorphism of human telomeric quadruplex structures

Targeting the c-Kit Promoter G-quadruplexes with 6-Substituted Indenoisoquinolines

First Evidence of a Functional Interaction between DNA Quadruplexes and Poly(ADP-ribose) Polymerase-1

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