Intramolecularly folded G-quadruplex and i-motif structures in the proximal promoter of the vascular endothelial growth factor gene

Guo, Kun; Gokhale, Vijay; Hurley, Laurence H.; Sun, Daekyu

doi:10.1093/nar/gkn380

Cited by 164 publications

(171 citation statements)

References 49 publications

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“…2C, Top, red arrowhead). Previous studies showed that such hypercleavages could occur at the Gs in the terminal G-quartet of a G-quadruplex, and the reason for that was not clear (22). Addition of GMP to the DNA did not alter the cleavage (blue vs. green peak).…”

Section: Resultsmentioning

confidence: 85%

Guanine-vacancy–bearing G-quadruplexes responsive to guanine derivatives

Zheng

Zhang

et al. 2015

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

104

144

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G-quadruplex structures formed by guanine-rich nucleic acids are implicated in essential physiological and pathological processes and nanodevices. G-quadruplexes are normally composed of four Gn (n ≥ 3) tracts assembled into a core of multiple stacked G-quartet layers. By dimethyl sulfate footprinting, circular dichroism spectroscopy, thermal melting, and photo-cross-linking, here we describe a unique type of intramolecular G-quadruplex that forms with one G 2 and three G 3 tracts and bears a guanine vacancy (G-vacancy) in one of the G-quartet layers. The G-vacancy can be filled up by a guanine base from GTP or GMP to complete an intact G-quartet by Hoogsteen hydrogen bonding, resulting in significant G-quadruplex stabilization that can effectively alter DNA replication in vitro at physiological concentration of GTP and Mg 2+ . A bioinformatic survey shows motifs of such G-quadruplexes are evolutionally selected in genes with unique distribution pattern in both eukaryotic and prokaryotic organisms, implying such G-vacancy-bearing G-quadruplexes are present and play a role in gene regulation. Because guanine derivatives are natural metabolites in cells, the formation of such G-quadruplexes and guanine fill-in (G-fill-in) may grant an environment-responsive regulation in cellular processes. Our findings thus not only expand the sequence definition of G-quadruplex formation, but more importantly, reveal a structural and functional property not seen in the standard canonical G-quadruplexes.G -quadruplexes are four-stranded structures formed in guanine-rich nucleic acids (1-3). Canonical G-quadruplexes are composed of four tracts of consecutive guanines connected by three loops. The guanines in the guanine tracts (G tracts) are packed in a core unit (Fig. 1A) of a stack of multiple G-quartet layers, each with four guanine bases connected by eight Hoogsteen hydrogen bonds (Fig. 1B). G-quadruplex-forming sequences are not randomly distributed in the mammalian genomes but concentrated at physiologically relevant positions (4): for instance, promoters, telomeres, and immuno-globulin switch regions. These facts suggest G-quadruplex structures have implications in physiological processes. Indeed, experimental investigations have demonstrated the physiological function of G-quadruplexes in many aspects (5-8).Studies on G-quadruplexes have mostly focused on sequences described by a consensus of G ≥3 (N 1-7 G ≥3 ) ≥3 , which can potentially form G-quadruplexes of three or more G-quartet layers with three loops of one to seven nucleotides (Fig. 1A) (9, 10). In recent years, the definition describing the capability of G-quadruplex formation has been broadened. Sequences with a loop up to 11 or 15 nucleotides were found capable of forming stable G-quadruplexes when the other two loops are sufficiently short (11, 12). The continuity of guanines in G tracts was also relaxed by the finding of G-quadruplexes with broken (13, 14) or bulged (15, 16) G tracts. Besides these intramolecular G-quadruplexes in single-stranded DNA (ssDNA), ...

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Section: Resultsmentioning

confidence: 85%

Guanine-vacancy–bearing G-quadruplexes responsive to guanine derivatives

Zheng

Zhang

et al. 2015

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

104

144

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“…It is evident that the spectra exhibited significant changes concomitant with pH change from 7.5 to 4.5. The CD spectra showed a large increase in ellipticity with a positive band near 288 nm and a negative peak at 262 nm at pH 4.5 and 5.5, which are the hallmark characteristics of i-motif structure (91)(92)(93). At pH 7.5, the positive maxima shifted to 278-280 nm with a drastic decrease in molar ellipticity, consistent with an unordered random-coiled structure.…”

Section: Resultsmentioning

confidence: 87%

Probing the Potential Role of Non-B DNA Structures at Yeast Meiosis-Specific DNA Double-Strand Breaks

Kshirsagar

Khan

Hosur

et al. 2017

Biophysical Journal

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A plethora of evidence suggests that different types of DNA quadruplexes are widely present in the genome of all organisms. The existence of a growing number of proteins that selectively bind and/or process these structures underscores their biological relevance. Moreover, G-quadruplex DNA has been implicated in the alignment of four sister chromatids by forming parallel guanine quadruplexes during meiosis; however, the underlying mechanism is not well defined. Here we show that a G/C-rich motif associated with a meiosis-specific DNA double-strand break (DSB) in Saccharomyces cerevisiae folds into G-quadruplex, and the C-rich sequence complementary to the G-rich sequence forms an i-motif. The presence of G-quadruplex or i-motif structures upstream of the green fluorescent protein-coding sequence markedly reduces the levels of gfp mRNA expression in S. cerevisiae cells, with a concomitant decrease in green fluorescent protein abundance, and blocks primer extension by DNA polymerase, thereby demonstrating the functional significance of these structures. Surprisingly, although S. cerevisiae Hop1, a component of synaptonemal complex axial/lateral elements, exhibits strong affinity to G-quadruplex DNA, it displays a much weaker affinity for the i-motif structure. However, the Hop1 C-terminal but not the N-terminal domain possesses strong i-motif binding activity, implying that the C-terminal domain has a distinct substrate specificity. Additionally, we found that Hop1 promotes intermolecular pairing between G/C-rich DNA segments associated with a meiosis-specific DSB site. Our results support the idea that the G/C-rich motifs associated with meiosis-specific DSBs fold into intramolecular G-quadruplex and i-motif structures, both in vitro and in vivo, thus revealing an important link between non-B form DNA structures and Hop1 in meiotic chromosome synapsis and recombination.

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“…Besides these above-mentioned i-Motifs, there are other promoter iMotifs that have been under study, like vascular endothelial growth factor promoter region can form an i-Motif in vitro at acidic pH [14].…”

Section: Editorialmentioning

confidence: 99%

Regulation of Oncogene Expression via Targeting i-Motif in Nucleic Acids

Agrawal¹

2017

J Pharmacovigilance

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Intramolecularly folded G-quadruplex and i-motif structures in the proximal promoter of the vascular endothelial growth factor gene

Cited by 164 publications

References 49 publications

Guanine-vacancy–bearing G-quadruplexes responsive to guanine derivatives

Guanine-vacancy–bearing G-quadruplexes responsive to guanine derivatives

Probing the Potential Role of Non-B DNA Structures at Yeast Meiosis-Specific DNA Double-Strand Breaks

Regulation of Oncogene Expression via Targeting i-Motif in Nucleic Acids

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