Bcl-2 Promoter Sequence G-Quadruplex Interactions with Three Planar and Non-Planar Cationic Porphyrins: TMPyP4, TMPyP3, and TMPyP2

Le, Vu; Nagesh, Narayana; Lewis, Edwin A.

doi:10.1371/journal.pone.0072462

Cited by 57 publications

(33 citation statements)

References 41 publications

(60 reference statements)

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“…In contrast, TMPyP2, a porphyrin derivative which shares chemical features with BRACO-19, i.e. a large aromatic surface and cationic moieties, but displays a different G-quadruplex binding mode and markedly lower G-quadruplex binding affinity (Han et al, 2001;Le et al, 2013), used here for comparison, did not induce any stop at G-rich regions and it did not modify the amount of the fulllength amplicons (lanes 3, Fig. 3).…”

Section: Namementioning

confidence: 83%

The Herpes Simplex Virus-1 genome contains multiple clusters of repeated G-quadruplex: Implications for the antiviral activity of a G-quadruplex ligand

et al. 2015

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Guanine-rich nucleic acids can fold into G-quadruplexes, secondary structures implicated in important regulatory functions at the genomic level in humans, prokaryotes and viruses. The remarkably high guanine content of the Herpes Simplex Virus-1 (HSV-1) genome prompted us to investigate both the presence of G-quadruplex forming sequences in the viral genome and the possibility to target them with G-quadruplex ligands to obtain anti-HSV-1 effects with a novel mechanism of action. Using biophysical, molecular biology and antiviral assays, we showed that the HSV-1 genome displays multiple clusters of repeated sequences that form very stable G-quadruplexes. These sequences are mainly located in the inverted repeats of the HSV-1 genome. Treatment of HSV-1 infected cells with the G-quadruplex ligand BRACO-19 induced inhibition of virus production. BRACO-19 was able to inhibit Taq polymerase processing at G-quadruplex forming sequences in the HSV-1 genome, and decreased intracellular viral DNA in infected cells. The last step targeted by BRACO-19 was viral DNA replication, while no effect on virus entry in the cells was observed. This work, presents the first evidence of extended G-quadruplex sites in key regions of the HSV-1 genome, indicates the possibility to block viral DNA replication by G-quadruplex-ligand and therefore provides a proof of concept for the use of G-quadruplex ligands as new anti-herpetic therapeutic options.

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Section: Namementioning

confidence: 83%

The Herpes Simplex Virus-1 genome contains multiple clusters of repeated G-quadruplex: Implications for the antiviral activity of a G-quadruplex ligand

et al. 2015

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“…H 2 -TMPyP2, with its pyridinium substituent perpendicular to the central tetrapyrrole of the porphyrin, does not interact with G4 DNA. H 2 -TMPyP3 is M a n u s c r i p t 14 capable of interaction with quadruplex DNA although less tightly than H 2 -TMPyP4 [101][102][103][104].…”

Section: Interaction Of Porphyrins With G-quadruplex Dnamentioning

confidence: 98%

Porphyrins in complex with DNA: Modes of interaction and oxidation reactions

Pratviel

2016

Coordination Chemistry Reviews

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“…In the light of the emerging evidence of the role of IM and G4 in regulating the genes involved in the control and progression of cell cycle and apoptosis, we propose that IM and G4 also have a regulatory role in neuroplasticity, including LTP, LTD, and synaptic scaling. In particular, one of the well-researched IM sequences is in Bcl-2 promoter 25,26 . Bcl-2 is known to be involved in apoptosis and autophagy, partly by inhibition of mTOR pathway 27 .…”

Section: Hypothesis: Ims and G4 May Play A Regulatory Role In Neuroplmentioning

confidence: 99%

Hypothesis: Regulation of neuroplasticity may involve I-motif and G-quadruplex DNA formation modulated by epigenetic mechanisms

Todorov

Cunha

2019

Medical Hypotheses

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Recent studies demonstrated the existence in vivo of various functional DNA structures that differ from the double helix. The G-quadruplex (G4) and intercalated motif (I-motif or IM) DNA structures are formed as knots where, correspondingly, guanines or cytosines on the same strand of DNA bind to each other. There are grounds to believe that G4 and IM sequences play a significant role in regulating gene expression considering their tendency to be found in or near regulatory sites (such as promoters, enhancers, and telomeres) as well as the correlation between the prevalence of G4 or IM conformations and specific phases of cell cycle. Notably, G4 and IM capable sequences tend to be found on the opposite strands of the same DNA site with at most one of the two structures formed at any given time. The recent evidence that K + , Mg 2+ concentrations directly affect IM formation (and likely G4 formation indirectly) lead us to believe that these structures may play a major role in synaptic plasticity of neurons, and, therefore, in a variety of central nervous system (CNS) functions including memory, learning, habitual behaviors, pain perception and others. Furthermore, epigenetic mechanisms, which have an important role in synaptic plasticity and memory formation, were also shown to influence formation and stability of G4s and IMs. Our hypothesis is that non-canonical DNA and RNA structures could be an integral part of neuroplasticity control via gene expression regulation at the level of transcription, translation and splicing. We propose that the regulatory activity of DNA IM and G4 structures is modulated by DNA methylation/demethylation of the IM and/or G4 sequences, which facilitates the switch between canonical and non-canonical conformation. Other neuronal mechanisms interacting with the formation and regulatory activity of non-canonical DNA and RNA structures, particularly G4, IM and triplexes, may involve microRNAs as well as ion and proton fluxes. We are proposing experiments in acute brain slices and in vivo to test our hypothesis. The proposed studies would provide new insights into fundamental neuronal mechanisms in health and disease and potentially open new avenues for treating mental health disorders. I-motif and G-quadruplexWhile double helix DNA structure (B-form) is the most common conformation, a variety of other forms are known to exist in vitro 1-5 . Some forms also appear to exist in vivo and were shown to have physiological significance 6 . Of those, G-quadruplex (G4) and intercalated motif (I-motif or IM) appear to be the most interesting. G4 is found in G-rich regulatory regions of the genome and was demonstrated to exist in vivo in several studies 6,7 . There is also evidence of its involvement in regulatory pathways 8 .IM, a form occurring primarily in C-rich regulatory regions and are characterized by C:C+ pairs. Hence IMs form more easily at lower pH. However, IMs can form at normal pH and are also affected by other factors, including ionic strengths (K + , Mg 2+ concentration in particula...

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Bcl-2 Promoter Sequence G-Quadruplex Interactions with Three Planar and Non-Planar Cationic Porphyrins: TMPyP4, TMPyP3, and TMPyP2

Cited by 57 publications

References 41 publications

The Herpes Simplex Virus-1 genome contains multiple clusters of repeated G-quadruplex: Implications for the antiviral activity of a G-quadruplex ligand

The Herpes Simplex Virus-1 genome contains multiple clusters of repeated G-quadruplex: Implications for the antiviral activity of a G-quadruplex ligand

Porphyrins in complex with DNA: Modes of interaction and oxidation reactions

Hypothesis: Regulation of neuroplasticity may involve I-motif and G-quadruplex DNA formation modulated by epigenetic mechanisms

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