Mutually Exclusive Formation of G-Quadruplex and i-Motif Is a General Phenomenon Governed by Steric Hindrance in Duplex DNA

Cui, Yunxi; Kong, De‐Ming; Ghimire, Chiran; Xu, Chunxiao; Mao, Hanbin

doi:10.1021/acs.biochem.6b00016

Cited by 89 publications

(90 citation statements)

References 32 publications

(73 reference statements)

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“…20–23 These structures have been shown to exist in a mutually exclusive fashion: while G-quadruplexes largely act as transcription repressors, recent studies suggest that i-motifs act as transcription activators. 24–27 Within the KRAS promoter, three potential DNA secondary structure-forming regions exist. On the basis of their proximity to the transcription start site, they are termed the Near-region (−129 to −159), Mid-region (−174 to −228), and Far-region (−238 to −275) (Figure 1A).…”

Section: Introductionmentioning

confidence: 99%

Insight into the Complexity of the i-Motif and G-Quadruplex DNA Structures Formed in the KRAS Promoter and Subsequent Drug-Induced Gene Repression

et al. 2017

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Activating KRAS mutations frequently occur in pancreatic, colorectal, and lung adenocarcinomas. While many attempts have been made to target oncogenic KRAS, no clinically useful therapies currently exist. Most efforts to target KRAS have focused on inhibiting the mutant protein; a less explored approach involves targeting KRAS at the transcriptional level. The promoter element of the KRAS gene contains a GC-rich nuclease hypersensitive site with three potential DNA secondary structure-forming regions. These are referred to as the Near-, Mid-, and Far-regions, on the basis of their proximity to the transcription start site. As a result of transcription-induced negative superhelicity, these regions can open up to form unique DNA secondary structures: G-quadruplexes on the G-rich strand and i-motifs on the C-rich strand. While the G-quadruplexes have been well characterized, the i-motifs have not been investigated as thoroughly. Here we show that the i-motif that forms in the C-rich Mid-region is the most stable and exists in a dynamic equilibrium with a hybrid i-motif/hairpin species and an unfolded hairpin species. The transcription factor heterogeneous nuclear ribonucleoprotein K (hnRNP K) was found to bind selectively to the i-motif species and to positively modulate KRAS transcription. Additionally, we identified a benzophenanthridine alkaloid that dissipates the hairpin species and destabilizes the interaction of hnRNP K with the Mid-region i-motif. This same compound stabilizes the three existing KRAS G-quadruplexes. The combined effect of the compound on the Mid-region i-motif and the G-quadruplexes leads to downregulation of KRAS gene expression. This dual i-motif/G-quadruplex-interactive compound presents a new mechanism to modulate gene expression.

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Section: Introductionmentioning

confidence: 99%

Insight into the Complexity of the i-Motif and G-Quadruplex DNA Structures Formed in the KRAS Promoter and Subsequent Drug-Induced Gene Repression

et al. 2017

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“…In addition, studies have revealed that the C-runs or cytosine residues in (G + C)-rich oligonucleotides significantly affect the formation (21) and stability of G4s (22,23). Mao and his research group show that for certain double-stranded sequences, the formation of G4s and i-motifs is mutually exclusive even under a favorable condition, which is mainly governed by steric hindrance in the double helix structure (24,25). Earlier studies also show that tetra-stranded i-motif structures formed by five consecutive cytosines have comparable stability to ten-base-pair-long duplexes (26).…”

Section: Introductionmentioning

confidence: 99%

Assembly of supramolecular DNA complexes containing both G-quadruplexes and i-motifs by enhancing the G-repeat-bearing capacity of i-motifs

et al. 2016

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The single-step assembly of supramolecular complexes containing both i-motifs and G-quadruplexes (G4s) is demonstrated. This can be achieved because the formation of four-stranded i-motifs appears to be little affected by certain terminal residues: a five-cytosine tetrameric i-motif can bear ten-base flanking residues. However, things become complex when different lengths of guanine-repeats are added at the 3′ or 5′ ends of the cytosine-repeats. Here, a series of oligomers d(XGiXC5X) and d(XC5XGiX) (X = A, T or none; i < 5) are designed to study the impact of G-repeats on the formation of tetrameric i-motifs. Our data demonstrate that tetramolecular i-motif structure can tolerate specific flanking G-repeats. Assemblies of these oligonucleotides are polymorphic, but may be controlled by solution pH and counter ion species. Importantly, we find that the sequences d(TGiAC5) can form the tetrameric i-motif in large quantities. This leads to the design of two oligonucleotides d(TG4AC7) and d(TGBrGGBrGAC7) that self-assemble to form quadruplex supramolecules under certain conditions. d(TG4AC7) forms supramolecules under acidic conditions in the presence of K+ that are mainly V-shaped or ring-like containing parallel G4s and antiparallel i-motifs. d(TGBrGGBrGAC7) forms long linear quadruplex wires under acidic conditions in the presence of Na+ that consist of both antiparallel G4s and i-motifs.

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“…Genetic and biochemical studies have shown that Hop1 protects DSB ends and recombination intermediates from exonucleolytic degradation (106,(116)(117)(118). Given the fact that both the i-motif and GQ form simultaneously within the same G/Crich motif (62), and Hop1 binds as a dimer to DNA (86), we hypothesize that the C-terminal domain from each monomer might interact with GQ and i-motif, respectively.…”

Section: Discussionmentioning

confidence: 99%

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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Mutually Exclusive Formation of G-Quadruplex and i-Motif Is a General Phenomenon Governed by Steric Hindrance in Duplex DNA

Cited by 89 publications

References 32 publications

Insight into the Complexity of the i-Motif and G-Quadruplex DNA Structures Formed in the KRAS Promoter and Subsequent Drug-Induced Gene Repression

Insight into the Complexity of the i-Motif and G-Quadruplex DNA Structures Formed in the KRAS Promoter and Subsequent Drug-Induced Gene Repression

Assembly of supramolecular DNA complexes containing both G-quadruplexes and i-motifs by enhancing the G-repeat-bearing capacity of i-motifs

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

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