Structures, folding patterns, and functions of intramolecular DNA G-quadruplexes found in eukaryotic promoter regions

Qin, Yong; Hurley, Laurence H.

doi:10.1016/j.biochi.2008.02.020

Cited by 419 publications

(406 citation statements)

References 128 publications

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“…Biological nanopores have been under extensive investigation as an emerging technology for next-generation DNA sequencing (12,46). Because numerous sequences of ssDNA, especially telomere and promoter regions of oncogenes (47,48), can fold into stable G-quadruplexes under physiological and nanopore measurement conditions, it is crucial to understand how these secondary structures interact with ion channel proteins. Consequently, the work presented here might provide considerable insight into the potential challenges that will arise as nanopore analysis of DNA molecules gains widespread application.…”

Section: Discussionmentioning

confidence: 99%

Single-molecule investigation of G-quadruplex folds of the human telomere sequence in a protein nanocavity

Fleming

Middleton

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

102

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Human telomeric DNA consists of tandem repeats of the sequence 5′-TTAGGG-3′ that can fold into various G-quadruplexes, including the hybrid, basket, and propeller folds. In this report, we demonstrate use of the α-hemolysin ion channel to analyze these subtle topological changes at a nanometer scale by providing structuredependent electrical signatures through DNA-protein interactions. Whereas the dimensions of hybrid and basket folds allowed them to enter the protein vestibule, the propeller fold exceeds the size of the latch region, producing only brief collisions. After attaching a 25-mer poly-2′-deoxyadenosine extension to these structures, unraveling kinetics also were evaluated. Both the locations where the unfolding processes occur and the molecular shapes of the G-quadruplexes play important roles in determining their unfolding profiles. These results provide insights into the application of α-hemolysin as a molecular sieve to differentiate nanostructures as well as the potential technical hurdles DNA secondary structures may present to nanopore technology.α-hemolysin nanopore | single-molecule detection N ucleic acids can fold into a myriad of secondary structures that depend on the primary sequence as well as the physical conditions in which the structures are prepared and characterized. One prime example of a multistructural sequence is human telomeric DNA comprising the repeat sequence 5′-TTAGGG-3′. This guanine-rich single-stranded sequence is known to fold into highly ordered nanostructures in the form of G-quadruplexes that feature the coordination of two alkali cations to three layers of G-tetrads formed by Hoogsteen hydrogen-bonded assemblies of four guanine bases ( Fig. 1A) (1, 2). G-quadruplexes provide a fascinating case in which the cation and physical context play critical roles in defining the overall structural topology as well as the stability of the fold. Guanine-rich sequences also are known to present challenges to PCR amplification and sequencingby-synthesis methods that require processive analysis of singlestranded DNA (ssDNA) because of the high thermodynamic stability of these folded structures.The following studies highlight the cation and contextdependent conditions in which the topology of the natural human telomere sequence 5′-TAGGG(TTAGGG) 3 TT-3′ is affected. In NaCl solution, NMR studies revealed a structure referred to as the basket fold (Fig. 1A) (4). Key features of this structure include an antiparallel strand arrangement with alternating syn and anti orientations of the guanosine glycosidic bonds and three tetrads linked by two edgewise loops and one diagonal loop. In contrast, NMR-based studies in KCl solution show that the same sequence folds predominantly to the hybrid-1 and hybrid-2 structures (Fig. 1A) (5-8). Characteristics of this structure are an antiparallel strand orientation with a 3+1 core of syn and anti G nucleotides yielding three tetrads. The loop topology of the hybrid fold consists of a double-chain reversal loop and two edgewise loops, in which hybr...

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Section: Discussionmentioning

confidence: 99%

Single-molecule investigation of G-quadruplex folds of the human telomere sequence in a protein nanocavity

Fleming

Middleton

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

102

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“…G-quadruplex DNA structures are highly attractive targets given the abundance of detailed information available regarding their structures, [20,21] thermodynamic stabilities, [22] and potential biological activities -some of which might be considered cancer-specific. [21,31,[33][34][35]46] A growing number of groups are targeting G-quadruplex DNA with small molecules hoping to inhibit cancer growth according to two distinct mechanisms (Fig. 4).…”

Section: G-quadruplex Dna As a Potential Drug Targetmentioning

confidence: 99%

“…First, the over-expression of oncogenes like c-Myc, c-Kit, and KRAS might be inhibited by promoter deactivation (Section 3). [33] The second, more extensively studied mechanism, is the inhibition of telomerase, a ribonucleoprotein complex that catalyzes the 3' extension of telomeric DNA (Sections 4 and 5). [20,35,41,42,46,47] …”

Section: G-quadruplex Dna As a Potential Drug Targetmentioning

confidence: 99%

“…[33,39] Since many of the genes containing potential quadruplex structures are overexpressed in cancer tissues, the deactivation of certain promoters by cell-permeable G-quadruplex ligands may provide a new route to anti-cancer therapies. [33] These results highlight the importance of developing highly selective G-quadruplex ligands that can differentiate between closely related G-quadruplex structures, as the deactivation of a large number of genes will result in non-specific toxicity like in the case of TMPyP4. [60,62] It remains an open question, however, if G-quadruplex structures in or near promoters are 'normal' regulatory elements utilized by transcriptional control machinery in vivo.…”

Section: Evidence For G-quadruplex Dna As a Modulator Of Gene Expressionmentioning

confidence: 99%

“…Intermolecular G-quadruplex structures have been proposed as intermediates or precursors of recombination and/or viral integration, [23,31,32] while intramolecular Gquadruplexes have been implicated in the regulation of gene expression and chromosome stability. [33][34][35] No consensus sequence for G-quadruplex folding has been experimentally determined, but approximately 370'000 sequences with the putative G-quadruplex-forming motif (G 3+ N 1-7 ) 4+ (where G = guanosine and N = any base) are dispersed throughout the human genome. [36,37] These sequences are concentrated in promoter regions, [14,38,39] introns, [36] 5' and 3' UTRs, [40] and at the ends of eukaryotic chromosomes.…”

Section: Introductionmentioning

confidence: 99%

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Targeting G-Quadruplex DNA with Small Molecules

Luedtke¹

2009

Chimia

101

105

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Despite a recent explosion of interest in G-quadruplex DNA, most fundamental questions regarding the possible presence and function of these intriguing structures in vivo remain unanswered. Cell-permeable G-quadruplex specific probes should provide researchers with new tools for studying these alternately folded DNA structures and their potential involvement in gene expression, chromosome stability, viral integration, and recombination. In this review, a survey of the binding affinity, specificity, and biological/pharmacological activities of some well-characterized G-quadruplex ligands is presented along with the potential importance of G-quadruplex DNA in vivo.134 CHIMIA 2009, 63, No. 3 Young AcAdemics in switzerlAnd PArt ii doi:10.2533doi:10. /chimia.2009doi:10. .134 Chimia 63 (2009 Despite a recent explosion of interest in G-quadruplex DNA, most fundamental questions regarding the possible presence and function of these intriguing structures in vivo remain unanswered. Cell-permeable Gquadruplex specific probes should provide researchers with new tools for studying these alternately folded DNA structures and their potential involvement in gene expression, chromosome stability, viral integration, and recombination. In this review, a survey of the binding affinity, specificity, and biological/pharmacological activities of some well-characterized G-quadruplex ligands is presented along with the potential importance of G-quadruplex DNA in vivo.

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Sequence, Stability, and Structure of G‐Quadruplexes and Their Interactions with Drugs

Chen

Yang

2012

CP Nucleic Acid Chemistry

115

146

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Although DNA is most widely known to store and pass along genetic information, the discovery of G-quadruplex structures has illuminated a new role of DNA in biology. DNA G-quadruplexes are four-stranded globular nucleic acid secondary structures formed in specific G-rich sequences with biological significance, such as human telomeres and oncogene promoters. This review focuses on the unimolecular DNA G-quadruplexes, which can readily form in solution under physiological conditions and are considered to be most biologically relevant. Available structural data show a great conformational diversity of unimolecular G-quadruplexes, amenable to small molecule drug targeting. The relationship of sequence, structure, and stability of unimolecular DNA G-quadruplexes, as well as the recent progress on interactions with small molecule compounds and insights into rational design of G-quadruplex-interactive molecules, will be discussed.

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Structures, folding patterns, and functions of intramolecular DNA G-quadruplexes found in eukaryotic promoter regions

Cited by 419 publications

References 128 publications

Single-molecule investigation of G-quadruplex folds of the human telomere sequence in a protein nanocavity

Single-molecule investigation of G-quadruplex folds of the human telomere sequence in a protein nanocavity

Targeting G-Quadruplex DNA with Small Molecules

Sequence, Stability, and Structure of G‐Quadruplexes and Their Interactions with Drugs

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