Insights into telomeric G-quadruplex DNA recognition by HMGB1 protein

Amato, Jussara; Cerofolini, Linda; Brancaccio, Diego; Giuntini, Stefano; Iaccarino, Nunzia; Zizza, Pasquale; Iachettini, Sara; Biroccio, Annamaria; Novellino, Ettore; Rosato, Antonio; Fragai, Marco; Luchinat, Claudio; Randazzo, Antonio; Pagano, Bruno

doi:10.1093/nar/gkz727

Cited by 41 publications

(39 citation statements)

References 57 publications

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“…Finally, we investigated the release of HMGB1 after three and six days of G4 ligand treatment. Noteworthy, HMGB1 was recently demonstrated to bind G4 DNA structures [28,29] thus we analyzed its intracellular accumulation. After 72 h no difference was observed with respect to untreated cells (Figure S5C), whereas after six days, the accumulation of HMGB1 was significantly detected in the presence of C066-3108 (3 µM) and BRACO-19 (3 µM) only in MDA-MB231 cells (Figure 5D).…”

Section: Resultsmentioning

confidence: 99%

G-Quadruplex Binders Induce Immunogenic Cell Death Markers in Aggressive Breast Cancer Cells

Somma

Amato

Iaccarino

et al. 2019

Cancers

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Background: DNA G-quadruplex (G4) structures represent potential anti-cancer targets. In this study, we compared the effect of two G4-targeting compounds, C066-3108 and the gold standard BRACO-19. Methods: In breast and prostate cancer cells, cytotoxicity induced by both molecules was measured by a sulforhodamine B assay. In breast cancer cells, cycle, apoptosis, the formation of G4 structures, calreticulin and high mobility group box 1 (HMGB1), as well as T cell activation, were analyzed by flow cytometry and adenosine triphosphate (ATP) by luminescence. Results: Both ligands inhibited cell survival and induced DNA damage. In MCF-7 cells, G4 ligands increased the subG0/G1 phase of the cell cycle inducing apoptosis and reduced intracellular ATP. In untreated MCF-7 cells, we observed a slight presence of G4 structures associated with the G2/M phase. In MDA-MB231 cells, G4 ligands decreased the G1 and enhanced the G2/M phase. We observed a decrease of intracellular ATP, calreticulin cell surface exposure and an increase of HMGB1, accompanied by T cell activation. Both compounds induced G4 structure formation in the subG0/G1 phase. Conclusions: Our data report similar effects for both compounds and the first evidence that G4 ligands induce the release of danger signals associated with immunogenic cell death and induction of T cell activation.

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Section: Resultsmentioning

confidence: 99%

G-Quadruplex Binders Induce Immunogenic Cell Death Markers in Aggressive Breast Cancer Cells

Somma

Amato

Iaccarino

et al. 2019

Cancers

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“…Therefore, to gain a complete and biologically relevant understanding of these interactions, it is important to study them as dynamic processes. In this frame, surface plasmon resonance (SPR) represents a powerful tool to study DNA–protein interactions, since it provides both equilibrium and kinetic information [ 32 , 33 ]. Indeed, SPR measures the kinetic rate constants of association ( k on ) and dissociation ( k off ), leading to the estimation of the equilibrium binding constant [ 34 ].…”

Section: Resultsmentioning

confidence: 99%

Toward G-Quadruplex-Based Anticancer Agents: Biophysical and Biological Studies of Novel AS1411 Derivatives

Ogloblina

Iaccarino

Capasso

et al. 2020

IJMS

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Certain G-quadruplex forming guanine-rich oligonucleotides (GROs), including AS1411, are endowed with cancer-selective antiproliferative activity. They are known to bind to nucleolin protein, resulting in the inhibition of nucleolin-mediated phenomena. However, multiple nucleolin-independent biological effects of GROs have also been reported, allowing them to be considered promising candidates for multi-targeted cancer therapy. Herein, with the aim of optimizing AS1411 structural features to find GROs with improved anticancer properties, we have studied a small library of AS1411 derivatives differing in the sequence length and base composition. The AS1411 derivatives were characterized by using circular dichroism and nuclear magnetic resonance spectroscopies and then investigated for their enzymatic resistance in serum and nuclear extract, as well as for their ability to bind nucleolin, inhibit topoisomerase I, and affect the viability of MCF-7 human breast adenocarcinoma cells. All derivatives showed higher thermal stability and inhibitory effect against topoisomerase I than AS1411. In addition, most of them showed an improved antiproliferative activity on MCF-7 cells compared to AS1411 despite a weaker binding to nucleolin. Our results support the hypothesis that the antiproliferative properties of GROs are due to multi-targeted effects.

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“…Currently, although it has been found that the stabilization of G4 structure can affect the telomerase enzyme activity with a resultant antineoplastic effect, the characterization of its folding intermediate structures formed in solution are still elusive at atomistic level 34 . In fact, for the propeller-type conformation, the G-triplex formation was considered as the less probable intermediate state 42 , while the most natural arrangement for such kind of topology is the vertical strand-slippage movement of the G-triplets that leads to two G-tetrad planes and one G-triad, as demonstrated by standard MDs 30 .…”

Section: Discussionmentioning

confidence: 99%

Folding intermediate states of the parallel human telomeric G-quadruplex DNA explored using Well-Tempered Metadynamics

Rocca

Palazzesi

Amato

et al. 2020

Sci Rep

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An increasingly comprehension of the folding intermediate states of DNA G-quadruplexes (G4s) iscurrently an important scientific challenge, especially for the human telomeric (h-tel) G4s-forming sequences, characterized by a highly polymorphic nature. Despite the G-triplex conformation was proposed as one of the possible folding intermediates for the antiparallel and hybrid h-tel G4s, for the parallel h-tel topology with an all-anti guanine orientation, a vertical strand-slippage involving the G-triplets was proposed in previous works through microseconds-long standard molecular dynamics simulations (MDs). Here, in order to get further insights into the vertical strand-slippage and the folding intermediate states of the parallel h-tel G4s, we have carried out a Well-Tempered Metadynamics simulation (WT-MetaD), which allowed us to retrieve an ensemble of six G4s having two/G-tetrad conformations derived by the G-triplets vertical slippage. The insights highlighted in this work are aimed at rationalizing the mechanistic characterisation of the parallel h-tel G4 folding process.G-quadruplexes 1,2 (G4s) are non canonical DNA structures present at the telomere ends and involved in the genome stability and in the inhibition of the telomerase enzyme, a reverse transcriptase responsible for the cellular immortalization 3,4 and up-regulated in ~85% of human tumors 3 . The evidence that G4s formation at the 3′-end of telomere DNA can effectively hamper telomerase from adding further repeats 3 suggests G4s as a promising target for anticancer therapy 5-7 . In order to identify new compounds as potential anticancer drugs, the structure-based drug design targeting G4s could be a crucial step in gaining accurate information about the structural features of G4s 8-13 . Unfortunately, the rational design of novel G4 binders is hampered both by the structural polymorphism of these non-canonical conformations and by the lack of a well-defined ligand binding site. Therefore, enhanced sampling methods, like Metadynamics, have been required in order to deeply define the ligand binding mode 14,15 . Monomolecular G4s of the human telomeric sequence d[AG 3 (TTAGGG) 3 ] (h-tel) can adopt different folding topologies according to the relative orientations of the four strands 16 . In fact, while the arrangement of the h-tel monomolecular G4s has been well characterized by NMR in Na + to adopt a basket-type conformation with the single strands assuming an antiparallel orientation 17 , in presence of K + ions the folding topology of the h-tel monomolecular G4s includes both parallel-stranded and hybrid (mixed parallel/antiparallel) conformations, raising the question of which conformation is biologically more favoured. In 2006, the NMR hybrid syn/anti conformation was proposed as the most favoured one under K + physiological conditions 18 , whose folding organization is different from that reported in K + ions by crystallography consisting, instead, in the parallel-stranded topology with three G-tetrads and three symmetrical external d(TTA) l...

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Insights into telomeric G-quadruplex DNA recognition by HMGB1 protein

Cited by 41 publications

References 57 publications

G-Quadruplex Binders Induce Immunogenic Cell Death Markers in Aggressive Breast Cancer Cells

G-Quadruplex Binders Induce Immunogenic Cell Death Markers in Aggressive Breast Cancer Cells

Toward G-Quadruplex-Based Anticancer Agents: Biophysical and Biological Studies of Novel AS1411 Derivatives

Folding intermediate states of the parallel human telomeric G-quadruplex DNA explored using Well-Tempered Metadynamics

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