Cationic Porphyrins Promote the Formation of i-Motif DNA and Bind Peripherally by a Nonintercalative Mechanism

Fedoroff, Oleg Yu.; Rangan, Anupama; Chemeris, Violetta V.; Hurley, Laurence H.

doi:10.1021/bi001528j

Cited by 106 publications

(89 citation statements)

References 47 publications

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“…Several small molecules have been shown to efficiently inhibit telomerase activity through the stabilization of G-quadruplex DNA (4, 5). Only two molecules that can stabilize both G-quadruplex and i-motif DNA have been identified (11,12). To our knowledge, a ligand that can selectively stabilize i-motif DNA but not G-quadruplex DNA has not been reported.…”

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confidence: 97%

“…The helix twists in a right-handed manner, and the distance between nearest base pairs is only 3.1 Å. In contrast with the G-rich quadruplex, little is known about the interaction of small ligands with this structure (2,11,12). Only two molecules, a porphyrin derivative and an acridine dimer, have been reported to stabilize both G-quadruplex and i-motif DNA via a nonintercalative mechanism (11,12).…”

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confidence: 99%

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Carboxyl-modified single-walled carbon nanotubes selectively induce human telomeric i-motif formation

Peng

Ren

et al. 2006

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

252

294

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As the leading nanodevice candidate, single-walled carbon nanotubes (SWNTs) have potential therapeutic applications in gene therapy and novel drug delivery. We found that SWNTs can inhibit DNA duplex association and selectively induce human telomeric i-motif DNA formation by binding to the 5-end major groove under physiological conditions or even at pH 8.0. SWNT binding to telomeric DNA was studied by UV melting, NMR, S1 nuclease cleavage, CD, and competitive FRET methods. These results suggest that SWNTs might have the intriguing potential to modulate human telomeric DNA structures in vivo, like biologically relevant B-A and B-Z DNA transitions, which is of great interest for drug design and cancer therapy. Since the discovery of the DNA i-motif, the formation and biological function of this unique structure have attracted much attention, and significant progress in characterizing the i-motif has been made in recent years (1, 2). The biological importance of the intramolecular i-motif is evidenced by its involvement in human telomeric and centromeric DNA structures and RNA intercalated structures, and by the discovery of several proteins that bind specifically to C-rich telomeric DNA fragments capable of forming i-motifs (2). Along with human telomeric G-quadruplex DNA, the i-motif has been an attractive drug target for cancer chemotherapy and for modulation of gene transcription (2-9). Human telomeres consist of tandem repeats of the double-stranded DNA sequence (5Ј-TTAGGG):(5Ј-CCCTAA) (3-9). The G-rich strand can form a four-stranded G-quadruplex consisting of G-quartets, whereas its complementary C-rich strand may adopt i-motif structures with intercalated C⅐C ϩ base pairs ( Fig. 1). Significantly, G-quadruplex formation was shown to inhibit the activity of telomerase, an enzyme that stabilizes chromosome ends by adding tandem telomeric DNA repeats to the 3Ј single-stranded overhangs (4,5,10). In contrast to the majority of normal human somatic cells, most tumor cells express telomerase, and telomerase expression is essential for their indefinite proliferative capacities. Therefore, the therapeutic targeting of telomerase activity has been considered a promising approach to cancer therapy (4, 5, 10). Several small molecules have been shown to efficiently inhibit telomerase activity through the stabilization of G-quadruplex DNA (4, 5). Only two molecules that can stabilize both G-quadruplex and i-motif DNA have been identified (11,12). To our knowledge, a ligand that can selectively stabilize i-motif DNA but not G-quadruplex DNA has not been reported.As the leading nanodevice candidate, single-walled carbon nanotubes (SWNTs) have potential applications ranging from gene therapy to novel drug delivery to membrane separation (13-17). B-Z DNA transition has been achieved on the surfaces of SWNTs (18). Recently we reported that SWNTs bind to the DNA major groove and can induce a sequence-dependent B-A DNA transition (19). In the present study we show that SWNTs can selectively stabilize human telomeric i-motif DN...

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confidence: 97%

mentioning

confidence: 99%

Carboxyl-modified single-walled carbon nanotubes selectively induce human telomeric i-motif formation

Peng

Ren

et al. 2006

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

252

294

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“…We have also recently demonstrated that G-quadruplex-interactive compounds such as TMPyP4 can also facilitate the formation of i-motif DNA and bind to the resulting structure by a nonintercalative mechanism (34). This provides an additional mechanism for intervention with small molecules in the conversion of c-myc NHE between duplex and alternative secondary structures.…”

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confidence: 98%

Induction of Duplex to G-quadruplex Transition in the c-myc Promoter Region by a Small Molecule

Rangan

Fedoroff

Hurley

2001

Journal of Biological Chemistry

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A major control element of the human c-myc oncogene is the nuclease-hypersensitive purine/pyrimidine-rich sequence. This double-stranded DNA fragment, corresponding to the 27-base pair segment in the nucleasehypersensitive element of the c-myc promoter region, forms a stable Watson-Crick double helix under physiological conditions. However, this duplex DNA can be effectively converted to G-quadruplex DNA by a small molecular weight ligand. Both intermolecular and intramolecular G-quadruplex forms can be induced by this ligand. Similar transitional changes are also observed with the duplex telomeric sequence from the Oxytricha species. These results provide additional support to the idea that G-quadruplex structures may play structural roles in vivo and also provide insight into novel methodologies for rational drug design. These structurally altered DNA elements might serve as regulatory signals in gene expression or in telomere dynamics and hence are promising targets for drug action.The protein product of the c-myc protooncogene plays a vital role in the process of cellular growth and differentiation (1). Deregulation of c-myc expression has been detected in many cancers and is believed to be an important step in tumorigenesis (2). The control of c-myc gene expression is a complex process and occurs at various steps of transcription, such as initiation, elongation, and attenuation, as well as during the post-transcriptional stages. Although the mechanisms involved in this regulation are not yet completely understood, a major control element of the human c-myc oncogene has been localized. This is a purine/pyrimidine-rich region located 115 bases upstream from the P1 promoter, which controls up to 95% of the total c-myc transcription (3, 4). This DNA segment is highly sensitive to DNase I and S1 nuclease (5, 6) and is termed the nuclease-hypersensitive element (NHE).1 The appearance of this hypersensitive site is coupled with transcription activation of the c-myc oncogene. Structural variations in the NHE can influence the binding of transcription factors. Transcription factors such as heterogenous nuclear ribonucleoprotein K and nucleoside diphosphate kinase B (7) bind sequence specifically to the pyrimidine-rich strand of the NHE and activate c-myc transcription (8). The transacting factors heterogenous nuclear ribonucleoprotein A/B (9) and cellular nucleic acid-binding protein (10) bind to the NHE and are shown to augment c-myc expression in vitro. Apart from protein factors, antisense oligonucleotides bind to the NHE and repress c-myc transcription in vitro (11,12). Formation of a colinear triplex between the synthetic oligonucleotide and the NHE was proposed to cause this observed repression in transcription.The NHE has a high potential to form atypical DNA structures under superhelical stress. It was proposed to be in a slow equilibrium between a Watson-Crick base-paired double helix and an atypical DNA structure (6). Many models have been suggested to explain the conformational changes observed in the NHE...

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“…Small molecules that stabilize G-quadruplexes are effective as telomerase inhibitors, and several series of compounds have been identified using techniques such as temperature melting fluorescence assays on oligonucleotides , electrophoresis analysis of quadruplex formation (Koeppel et al, 2001), electrospray ionization mass spectrometry (Rosu et al, 2003a), and the telomeric repeat amplification protocol that measures telomerase activity in cell extracts (Gomez et al, 2002) (for review, see Guittat et al, 2004). The ligands that stabilize G-quadruplex structures include cationic porphyrins (Han et al, 1999Dixon et al, 2007), perylenes (Fedoroff et al, 2000), amidoanthracene-9,10-diones (Perry et al, 1998), 2,7-disubstituted amidofluorenones (Perry et al, 1999), acridines Harrison et al, 2003), ethidium derivatives (Koeppel et al, 2001;Rosu et al, 2003a), disubstituted triazines , fluoroquinoanthroxazines (Kim et al, 2003a), indoloquinolines (Caprio et al, 2000), dibenzophenanthrolines , bisquinacridines (Teulade-Fichou et al, 2003), pentacyclic acridinium (Gowan et al, 2001), telomestatin (Shin-ya et al, 2001), and the recently discovered bisquinolinium derivatives Pennarun et al, 2005;De Cian et al, 2007) (for review, see Kerwin, 2000;Cuesta et al, 2003;Guittat et al, 2004;Pendino et al, 2006). Because of the peculiar features of the quadruplex structure, compared with classic double-stranded B-DNA, a selective recognition of telomeric G-quadruplex by small-molecule ligands should be possible Parkinson et al, 2002;Clark et al, 2003;Ambrus et al, 2006).…”

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A New Steroid Derivative Stabilizes G-Quadruplexes and Induces Telomere Uncapping in Human Tumor Cells

Brassart

Gómez²,

Cian³

et al. 2007

Molecular Pharmacology

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Human telomeric DNA consists of tandem repeats of the sequence d(TTAGGG) with a 3Ј single-stranded extension (the G-overhang). The stabilization of G-quadruplexes in the human telomeric sequence by small-molecule ligands inhibits the activity of telomerase and results in telomere uncapping, leading to senescence or apoptosis of tumor cells. Therefore, the search for new and selective G-quadruplex ligands is of considerable interest because a selective ligand might provide a telomere-targeted therapeutic approach to treatment of cancer. We have screened a bank of derivatives from natural and synthetic origin using a temperature fluorescence assay and have identified two related compounds that induce G-quadruplex stabilization: malouetine and steroid FG. These steroid derivatives have nonplanar and nonaromatic structures, different from currently known G-quadruplex ligands. Malouetine is a natural product isolated from the leaves of Malouetia bequaaertiana E. Woodson and is known for its curarizing and DNAbinding properties. Steroid FG, a funtumine derivative substituted with a guanylhydrazone moiety, interacted selectively with the telomeric G-quadruplex in vitro. This derivative induced senescence and telomere shortening of HT1080 tumor cells at submicromolar concentrations, corresponding to the phenotypic inactivation of telomerase activity. In addition, steroid FG induced a rapid degradation of the telomeric G-overhang and the formation of anaphase bridges, characteristics of telomere uncapping. Finally, the expression of protection of telomere 1 (POT1) induced resistance to the growth effect of steroid FG. These results indicate that these steroid ligands represent a new class of telomere-targeted agents with potential as antitumor drugs.

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Cationic Porphyrins Promote the Formation of i-Motif DNA and Bind Peripherally by a Nonintercalative Mechanism

Cited by 106 publications

References 47 publications

Carboxyl-modified single-walled carbon nanotubes selectively induce human telomeric i-motif formation

Carboxyl-modified single-walled carbon nanotubes selectively induce human telomeric i-motif formation

Induction of Duplex to G-quadruplex Transition in the c-myc Promoter Region by a Small Molecule

A New Steroid Derivative Stabilizes G-Quadruplexes and Induces Telomere Uncapping in Human Tumor Cells

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