Tiny telomere DNA

Ren, Jinsong; Qu, Xiaogang; Trent, John O.; Chaires, Jonathan B.

doi:10.1093/nar/30.11.2307

Cited by 78 publications

(97 citation statements)

References 38 publications

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“…In contrast to the hyperchromic shift at 260 nm associated with melting of duplex DNA, the melting of G-quadruplex DNA is associated with a hypochromic shift at 295 nm (23)(24)(25)(26). Consequently, the thermally induced structural transitions of G-quadruplexes into single-stranded forms can be readily detected by examining their characteristic UV melting profiles at 295 nm.…”

Section: Resultsmentioning

confidence: 99%

G-Quadruplexes Induce Apoptosis in Tumor Cells

Lin

et al. 2006

Cancer Research

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Several G-rich oligodeoxynucleotides (ODNs), which are capable of forming G-quadruplexes, have been shown to exhibit antiproliferative activity against tumor cell lines and antitumor activity in nude mice carrying prostate and breast tumor xenografts. However, the molecular basis for their antitumor activity remains unclear. In the current study, we showed that a variety of telomeric G-tail oligodeoxynucleotides (TG-ODNs) exhibited antiproliferative activity against many tumor cells in culture. Systematic mutational analysis of the TG-ODNs suggests that the antiproliferative activity depends on the G-quadruplex conformation of these TG-ODNs. TG-ODNs were also shown to induce poly(ADPribose) polymerase-1 cleavage, phosphatidylserine flipping, and caspase activation, indicative of induction of apoptosis. TG-ODN-induced apoptosis was largely ataxia telangiectasia mutated (ATM) dependent. Furthermore, TG-ODN-induced apoptosis was inhibited by the c-Jun NH 2 -terminal kinase (JNK) inhibitor SP600125. Indeed, TG-ODNs were shown to activate the JNK pathway in an ATM-dependent manner as evidenced by elevated phosphorylation of JNK and c-Jun. Interestingly, a number of G-quadruplex ODNs (GQ-ODN) derived from nontelomeric sequences also induced ATM/JNKdependent apoptosis, suggesting a possible common mechanism of tumor cell killing by GQ-ODNs. (Cancer Res 2006; 66(24): 11808-16)

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Section: Resultsmentioning

confidence: 99%

G-Quadruplexes Induce Apoptosis in Tumor Cells

Lin

et al. 2006

Cancer Research

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“…A switching between parallel and antiparallel quadruplexes has been observed by Raman spectroscopy and depends on the concentrations of Na ϩ and K ϩ (36). More recently, multiple species for a human telomeric sequence have been discovered by UV spectroscopy (13). The antiparallel structure for HTIQ was determined by NMR spectroscopy at high (Ϸmillimolar) concentration, so it is possible that intermolecular interactions may help stabilize one particular structure.…”

Section: Conformationsmentioning

confidence: 99%

“…This apparent contradiction may actually be a reflection of a conformational preference for the HTIQ in sodium vs. potassium, or a direct consequence of other experimental differences between the two studies. Chaires and coworkers (13) have provided evidence, based on detailed analysis of absorbance spectra, that for a DNA quadruplex multiple species coexist in sodium buffer. Studies that probe the folding and unfolding processes of the quadruplex will provide insight into such structural heterogeneity.…”

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confidence: 99%

Studies on the structure and dynamics of the human telomeric G quadruplex by single-molecule fluorescence resonance energy transfer

Ying

Green

et al. 2003

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

293

298

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We have investigated the structure and unfolding kinetics of the human telomeric intramolecular G quadruplex by using singlemolecule fluorescence resonance energy transfer. An exploration of conformational heterogeneity revealed two stable folded conformations, in both sodium-and potassium-containing buffers, with small differences between their enthalpies and entropies. Both folded conformations can be opened by the addition of a 21-base complementary DNA oligonucleotide. The unfolding of both substates occurs at the same rate, which showed dependence on the monovalent metal cation present. Temperature-dependence studies in 100 mM KCl gave an apparent activation enthalpy and entropy of 6.4 ؎ 0.4 kcal⅐mol ؊1 and ؊52.3 ؎ 1.4 cal⅐mol ؊1 ⅐K ؊1 , respectively, indicating that the unfolding is entropically driven and can occur easily. In contrast, in 100 mM NaCl the respective values are 14.9 ؎ 0.2 kcal⅐mol ؊1 and ؊23.0 ؎ 0.8 cal⅐mol ؊1 ⅐K ؊1 , suggesting a more significant enthalpic barrier. Molecular modeling suggests that the two species are likely to be the parallel and antiparallel quadruplex structures. The unfolding free energy barrier is estimated to be between 3 and 15 k BT based on Kramers' theory. We conclude that under near-physiological conditions these structures coexist and can interconvert on a minute time scale. DNA sequences with stretches of multiple guanines can form four-stranded structures called quadruplexes (1). The evidence is growing that quadruplexes may be important for several biological mechanisms (1-8). Evidence supports the occurrence of quadruplexes in the cell nucleus (9), and, furthermore, a recent study suggests that particular quadruplexes may have the potential to control gene expression (10). The intramolecular DNA quadruplex based on the human telomeric repeat sequence, d(TTAGGG), has been the subject of extensive biophysical and biological studies. It has been demonstrated, in vitro, that formation of this structure impedes the extension mechanism of human telomerase (3). Furthermore, stabilization of this quadruplex may be a natural or unnatural mechanism to influence the regulation of teleomeres at the ends of chromosomes. Because telomerase function and telomere maintenance are critical for the division of cancer cells, the human telomeric intramolecular quadruplex (HTIQ) is being seriously considered as a potential molecular target for the development of novel anticancer agents (7,8). Detailed structural studies have provided evidence for two distinct folds for the HTIQ in the presence of sodium and potassium ions (11,12). An NMR spectroscopic study, where the dominant monovalent cation was sodium, showed that the HTIQ exists predominantly with an antiparallel arrangement of strands with a diagonal loop across a terminal tetrad and edgewise loops (11) (see Fig. 7A, which is published as supporting information on the PNAS web site). In contrast, a recent x-ray crystal structure of the same oligonucleotide, in the presence of potassium, shows all four strands to be parallel ...

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“…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)(3)(4)(5)(6)(7)(8)(9). Human telomeres consist of tandem repeats of the double-stranded DNA sequence (5Ј-TTAGGG):(5Ј-CCCTAA) (3)(4)(5)(6)(7)(8)(9).…”

mentioning

confidence: 99%

“…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)(3)(4)(5)(6)(7)(8)(9). Human telomeres consist of tandem repeats of the double-stranded DNA sequence (5Ј-TTAGGG):(5Ј-CCCTAA) (3)(4)(5)(6)(7)(8)(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.…”

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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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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Tiny telomere DNA

Cited by 78 publications

References 38 publications

G-Quadruplexes Induce Apoptosis in Tumor Cells

G-Quadruplexes Induce Apoptosis in Tumor Cells

Studies on the structure and dynamics of the human telomeric G quadruplex by single-molecule fluorescence resonance energy transfer

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

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