Molecular modeling and biophysical analysis of the c-MYC NHE-III1 silencer element

Cashman, Derek J.; Buscaglia, Robert; Freyer, Matthew W.; Dettler, Jamie M.; Hurley, Laurence H.; Lewis, Edwin A.

doi:10.1007/s00894-007-0254-z

Cited by 33 publications

(34 citation statements)

References 33 publications

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“…Previous studies involving i-motif-forming oligonucleotides at acidic pHs have determined that the signature CD spectra specific for an i-motif secondary structure consists of a maximum positive peak within 280–288 nm and a negative peak within 260–267 nm 19,62,64,71…”

Section: Resultsmentioning

confidence: 99%

“…The capping structures formed by the large 8:5:7 loop conformation of the bcl-2 i-motif may be responsible for the high transitional pH (6.6) and stability. Similarly, the well-characterized c-myc i-motif also utilizes six cytosine tracts, which results in a 6:2:6 loop conformation, and, as in the bcl-2 i-motif, these large lateral loops most likely contribute to the high transitional pH of 6.5–6.8 60,62. This is in contrast to the previously characterized smaller i-motif loop conformation of 2:(3–4):2 for the VEGF ,49 RET ,56 and Rb 63 structures, which exhibit lower transitional pHs of 5.9, 6.4, and 5.9, respectively.…”

Section: Discussionmentioning

confidence: 99%

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The i-Motif in the bcl-2 P1 Promoter Forms an Unexpectedly Stable Structure with a Unique 8:5:7 Loop Folding Pattern

et al. 2009

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Transcriptional regulation of the bcl-2 proto-oncogene is highly complex, with the majority of transcription driven by the P1 promoter site and the interaction of multiple regulatory proteins. A guanine-and cytosine-rich (GC-rich) region directly upstream of the P1 site has been shown to be integral to bcl-2 promoter activity, as deletion or mutation of this region significantly increases transcription. This GC-rich element consists of six contiguous runs of guanines and cytosines that have the potential to adopt DNA secondary structures, the G-quadruplex and i-motif, respectively. Our laboratory has previously demonstrated that the polypurine-rich strand of the bcl-2 promoter can form a mixture of three different G-quadruplex structures. In this current study, we demonstrate that the complementary polypyrimidine-rich strand is capable of forming one major intramolecular imotif DNA secondary structure with a transition pH of 6.6. Characterization of the i-motif folding pattern using mutational studies coupled with circular dichroic spectra and thermal stability analyses revealed an 8:5:7 loop conformation as the predominant structure at pH 6.1. The folding pattern was further supported by chemical footprinting with bromine. In addition, a novel assay involving the sequential incorporation of a fluorescent thymine analog at each thymine position provided evidence of a capping structure within the top loop region of the i-motif. The potential of the GC-rich element within the bcl-2 promoter region to form DNA secondary structures suggests that the transition from the B-DNA to non-B-DNA conformation may play an important role in bcl-2 transcriptional regulation. Furthermore, the two adjacent large lateral loops in the i-motif structure provide an unexpected opportunity for protein and small molecule recognition.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The i-Motif in the bcl-2 P1 Promoter Forms an Unexpectedly Stable Structure with a Unique 8:5:7 Loop Folding Pattern

et al. 2009

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“…G-quadruplex DNA was discovered in eukaryotic telomere and oncogene promoters through a G-quadruplex-specific antibody and was shown to be a potential small molecule target [10–11]. c-myc transcription is primarily regulated by a 27-base G-rich sequence in the NHE III1 (nuclease hypersensitivity element III1) region [12–13]. This sequence is located upstream (−142 to −115 bp) of the P1 promoter in the human c-myc oncogene and controls 85–90% of c-myc transcription [14].…”

Section: Introductionmentioning

confidence: 99%

Quinazoline derivative QPB-15e stabilizes the c-myc promoter G-quadruplex and inhibits tumor growth in vivo

et al. 2016

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The ribozyme-sensitive element NHE-III1 in the P1 promoter region of the important proto-oncogene c-myc contains many guanine (G)-rich sequences. Induction and stabilization of the G-quadruplex formed by NHE-III1 can downregulate c-myc expression. In the present study, we found that QPB-15e, a quinazoline derivative designed and synthesized by our laboratory, binds to and stabilizes the c-myc G-quadruplex in vitro, thereby inhibiting double-stranded DNA replication, downregulating c-myc gene expression and arresting cancer cell proliferation. PCR termination experiments showed that QPB-15e blocked double-stranded DNA replication by inducing or stabilizing the c-myc G-quadruplex. FRET-melting further confirmed that QPB-15e improved the stability of the G-quadruplex, and CD spectroscopy indicated that the compound interacted directly with the G-rich sequence. In competitive dialysis experiments, QPB-15e bound preferentially to quadruplex DNA in various structures, especially the G-quadruplex within the c-myc promoter region. Moreover, QPB-15e reduced the weights and volumes of tumors transplanted into nude mice. These findings strongly suggest that QPB-15e is a c-myc G-quadruplex ligand with anti-tumor properties, and may be efficacious for treating cancer in humans.

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“…Exclusive binding of flat TMPyP4 cation (meso-5,10,15, 20-Tetrakis-(N-methyl-4-pyridyl)) porphine porphyrin to DNA is a subject of interest in a number of fields, including molecular biology, genomics and pharmaceutical science [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

Zn Ions Change Binding Mode of TOEPyP4 with DNA and Cause DNA Transition from B to C and Zn-Like Conformations

Monaselidze¹,

Gorgoshidze²,

Khachidze³

et al. 2013

AJAC

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It is known that at low concentrations of TMPyP4, this porphyrin predominantly intercalates between GC pairs at GC-rich sites of duplex DNA and G-quadruplexes of various constructions, and stabilizes these structures. However, there are still some arguable suggestions about the exact binding sites and modes of TMPyP4 to GC-rich regions of DNA in case of helation of divalent ions with help of the porphrin, which makes porphyrin structure asymmetric. We examined TOEPyP4-analogue of TMPyP4-and studied interaction of TOEPyP4 into the calf thymus DNA at presence of nanomole concentrations of one of the most important microelements in cell vital function-Zn ion. On the basis of CD and absorption spectra of the DNA-TOEPyP4 mixture, it was determined that nanomole concentrations of Zn ions changed porphyrin intercalative binding mode to some external binding modes, which initiated transition of the canonic B conformation of DNA into C-like conformation, and incubation of the (DNA-TOEP4) + Zn mixture at 37˚C caused B-Z-like transition, but no transition was observed for the DNA-TOEPyP4 mixture. In particular, at 10 mM·NaCl, TOEPyP4/DNA = 0.02, the binding mode change was observed in the concentration range from 150 to 300 nM·Zn, and the B-C-like transition occurred from 150 to 600 nM·Zn. The B-Z transition at TOEPyP4/DNA = 0.015, Zn/DNA = 0.015, NaCI 10 mM, T = 37˚C was observed within incubation time interval from 0.3 to 20 hours, and maximal percents of Z-like form was seen when incubation time interval was from 5 to 6 hours.

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Molecular modeling and biophysical analysis of the c-MYC NHE-III1 silencer element

Cited by 33 publications

References 33 publications

The i-Motif in the bcl-2 P1 Promoter Forms an Unexpectedly Stable Structure with a Unique 8:5:7 Loop Folding Pattern

The i-Motif in the bcl-2 P1 Promoter Forms an Unexpectedly Stable Structure with a Unique 8:5:7 Loop Folding Pattern

Quinazoline derivative QPB-15e stabilizes the c-myc promoter G-quadruplex and inhibits tumor growth in vivo

Zn Ions Change Binding Mode of TOEPyP4 with DNA and Cause DNA Transition from B to C and Zn-Like Conformations

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