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Dr. David Monchaud
Institut de Chimie Moléculaire, ICMUB CNRS UMR6302, UBFC, Dijon, France

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Research article
Published: 04 August 2021 in Journal of the American Chemical Society
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The quest for small molecules that strongly bind to G-quadruplex-DNA (G4), so-called G4 ligands, has invigorated the G4 research field from its very inception. Massive efforts have been invested to discover or rationally design G4 ligands, evaluate their G4-interacting properties in vitro through a series of now widely accepted and routinely implemented assays, and use them as innovative chemical biology tools to interrogate cellular networks that might involve G4s. In sharp contrast, only uncoordinated efforts aimed at developing small molecules that destabilize G4s have been invested to date, even though it is now recognized that such molecular tools would have tremendous application in neurobiology as many genetic and age-related diseases are caused by an overrepresentation of G4s. Herein, we report on our efforts to develop in vitro assays to reliably identify molecules able to destabilize G4s. This workflow comprises the newly designed G4-unfold assay, adapted from the G4-helicase assay implemented with Pif1, as well as a series of biophysical and biochemical techniques classically used to study G4/ligand interactions (CD, UV–vis, PAGE, and FRET-melting), and a qPCR stop assay, adapted from a Taq-based protocol recently used to identify G4s in the genomic DNA of Schizosaccharomyces pombe. This unique, multipronged approach leads to the characterization of a phenylpyrrolocytosine (PhpC)-based G-clamp analog as a prototype of G4-disrupting small molecule whose properties are validated through many different and complementary in vitro evaluations.

ACS Style

Jérémie Mitteaux; Pauline Lejault; Filip Wojciechowski; Alexandra Joubert; Julien Boudon; Nicolas Desbois; Claude P. Gros; Robert H. E. Hudson; Jean-Baptiste Boulé; Anton Granzhan; David Monchaud. Identifying G-Quadruplex-DNA-Disrupting Small Molecules. Journal of the American Chemical Society 2021, 143, 12567 -12577.

AMA Style

Jérémie Mitteaux, Pauline Lejault, Filip Wojciechowski, Alexandra Joubert, Julien Boudon, Nicolas Desbois, Claude P. Gros, Robert H. E. Hudson, Jean-Baptiste Boulé, Anton Granzhan, David Monchaud. Identifying G-Quadruplex-DNA-Disrupting Small Molecules. Journal of the American Chemical Society. 2021; 143 (32):12567-12577.

Chicago/Turabian Style

Jérémie Mitteaux; Pauline Lejault; Filip Wojciechowski; Alexandra Joubert; Julien Boudon; Nicolas Desbois; Claude P. Gros; Robert H. E. Hudson; Jean-Baptiste Boulé; Anton Granzhan; David Monchaud. 2021. "Identifying G-Quadruplex-DNA-Disrupting Small Molecules." Journal of the American Chemical Society 143, no. 32: 12567-12577.

Journal article
Published: 01 August 2021 in CCS Chemistry
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Massive efforts are currently being invested to improve the performance, versatility, and scope of applications of nucleic acid catalysts. G-quadruplex (G4)/hemin DNAzymes are of particular interest owing to their structural programmability and chemical robustness. However, the optimization of their catalytic efficiency still weak, accompanied by unclear activation mechanism. Here, we designed a series of parallel G4s with different proximal cytosine (dC) derivatives to fine-tune the hemin binding pocket for G4-DNAzymes. Combining theoretical and experimental methods, we assessed the dependence of catalytic enhancement on electronic properties of the proximal dCs, and demonstrated how the proximal dCs activate the catalytic proficiency. These results provide interesting clues to recapitulate the push-pull mechanism at the very heart of peroxidase activity and thus devise a new strategy to design highly competent DNA catalysts whose performances are in the same order as protease. Download figure Download PowerPoint

ACS Style

Jielin Chen; Jiawei Wang; Stephanie C. C. van der Lubbe; Mingpan Cheng; Dehui Qiu; David Monchaud; Jean-Louis Mergny; Célia Fonseca Guerra; Huangxian Ju; Jun Zhou. A Push–Pull Mechanism Helps Design Highly Competent G-Quadruplex-DNA Catalysts. CCS Chemistry 2021, 3, 2183 -2193.

AMA Style

Jielin Chen, Jiawei Wang, Stephanie C. C. van der Lubbe, Mingpan Cheng, Dehui Qiu, David Monchaud, Jean-Louis Mergny, Célia Fonseca Guerra, Huangxian Ju, Jun Zhou. A Push–Pull Mechanism Helps Design Highly Competent G-Quadruplex-DNA Catalysts. CCS Chemistry. 2021; 3 (8):2183-2193.

Chicago/Turabian Style

Jielin Chen; Jiawei Wang; Stephanie C. C. van der Lubbe; Mingpan Cheng; Dehui Qiu; David Monchaud; Jean-Louis Mergny; Célia Fonseca Guerra; Huangxian Ju; Jun Zhou. 2021. "A Push–Pull Mechanism Helps Design Highly Competent G-Quadruplex-DNA Catalysts." CCS Chemistry 3, no. 8: 2183-2193.

Journal article
Published: 02 July 2021 in NAR Cancer
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About 10–15% of all human cancer cells employ a telomerase-independent recombination-based telomere maintenance method, known as alternative lengthening of telomere (ALT), of which the full mechanism remains incompletely understood. While implicated in previous studies as the initiating signals for ALT telomere repair, the prevalence of non-canonical nucleic acid structures in ALT cancers remains unclear. Extending earlier reports, we observe higher levels of DNA/RNA hybrids (R-loops) in ALT-positive (ALT+) compared to telomerase-positive (TERT+) cells. Strikingly, we observe even more pronounced differences for an associated four-stranded nucleic acid structure, G-quadruplex (G4). G4 signals are found at the telomere and are broadly associated with telomere length and accompanied by DNA damage markers. We establish an interdependent relationship between ALT-associated G4s and R-loops and confirm that these two structures can be spatially linked into unique structures, G-loops, at the telomere. Additionally, stabilization of G4s and R-loops cooperatively enhances ALT-activity. However, co-stabilization at higher doses resulted in cytotoxicity in a synergistic manner. Nuclear G4 signals are significantly and reproducibly different between ALT+ and TERT+ low-grade glioma tumours. Together, we present G4 as a novel hallmark of ALT cancers with potential future applications as a convenient biomarker for identifying ALT+ tumours and as therapeutic targets.

ACS Style

Sunny Y Yang; Emily Y C Chang; Joanne Lim; Harwood H Kwan; David Monchaud; Stephen Yip; Peter C Stirling; Judy M Y Wong. G-quadruplexes mark alternative lengthening of telomeres. NAR Cancer 2021, 3, zcab031 .

AMA Style

Sunny Y Yang, Emily Y C Chang, Joanne Lim, Harwood H Kwan, David Monchaud, Stephen Yip, Peter C Stirling, Judy M Y Wong. G-quadruplexes mark alternative lengthening of telomeres. NAR Cancer. 2021; 3 (3):zcab031.

Chicago/Turabian Style

Sunny Y Yang; Emily Y C Chang; Joanne Lim; Harwood H Kwan; David Monchaud; Stephen Yip; Peter C Stirling; Judy M Y Wong. 2021. "G-quadruplexes mark alternative lengthening of telomeres." NAR Cancer 3, no. 3: zcab031.

Journal article
Published: 17 June 2021 in Aging
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The G-quadruplex (G4-DNA or G4) is a secondary DNA structure formed by DNA sequences containing multiple runs of guanines. While it is now firmly established that stabilized G4s lead to enhanced genomic instability in cancer cells, whether and how G4s contribute to genomic instability in brain cells is still not clear. We previously showed that, in cultured primary neurons, small-molecule G4 stabilizers promote formation of DNA double-strand breaks (DSBs) and downregulate the Brca1 gene. Here, we determined if G4-dependent Brca1 downregulation is unique to neurons or if the effects in neurons also occur in astrocytes and microglia. We show that primary neurons, astrocytes and microglia basally exhibit different G4 landscapes. Stabilizing G4-DNA with the G4 ligand pyridostatin (PDS) differentially modifies chromatin structure in these cell types. Intriguingly, PDS promotes DNA DSBs in neurons, astrocytes and microglial cells, but fails to downregulate Brca1 in astrocytes and microglia, indicating differences in DNA damage and repair pathways between brain cell types. Taken together, our findings suggest that stabilized G4-DNA contribute to genomic instability in the brain and may represent a novel senescence pathway in brain aging.

ACS Style

Natalie Tabor; Conelius Ngwa; Jeremie Mitteaux; Matthew D. Meyer; Jose F. Moruno-Manchon; Liang Zhu; Fudong Liu; David Monchaud; Louise D. McCullough; Andrey S. Tsvetkov. Differential responses of neurons, astrocytes, and microglia to G-quadruplex stabilization. Aging 2021, 13, 15917 -15941.

AMA Style

Natalie Tabor, Conelius Ngwa, Jeremie Mitteaux, Matthew D. Meyer, Jose F. Moruno-Manchon, Liang Zhu, Fudong Liu, David Monchaud, Louise D. McCullough, Andrey S. Tsvetkov. Differential responses of neurons, astrocytes, and microglia to G-quadruplex stabilization. Aging. 2021; 13 (12):15917-15941.

Chicago/Turabian Style

Natalie Tabor; Conelius Ngwa; Jeremie Mitteaux; Matthew D. Meyer; Jose F. Moruno-Manchon; Liang Zhu; Fudong Liu; David Monchaud; Louise D. McCullough; Andrey S. Tsvetkov. 2021. "Differential responses of neurons, astrocytes, and microglia to G-quadruplex stabilization." Aging 13, no. 12: 15917-15941.

Research article
Published: 29 April 2021 in ACS Chemical Biology
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G-quadruplexes (G4s) continue to gather wide attention in the field of chemical biology as their prevalence in the human genome and transcriptome strongly suggests that they play key regulatory roles in cell biology. G4-specific, cell-permeable small molecules (G4-ligands) innovatively permit the interrogation of cellular circuitries in order to assess to what extent G4s influence cell fate and functions. Here, we report on multivalent, biomimetic G4-ligands referred to as TASQs that enable both the isolation and visualization of G4s in human cells. Two biotinylated TASQs, BioTASQ and BioCyTASQ, are indeed efficient molecular tools to isolate G4s from mixtures of nucleic acids through simple affinity capture protocols and to image G4s in cells via a biotin/avidin pretargeted imaging system first applied here to G4s, found to be a reliable alternative to in situ click chemistry.

ACS Style

Francesco Rota Sperti; Thibaut Charbonnier; Pauline Lejault; Joanna Zell; Claire Bernhard; Ibai E. Valverde; David Monchaud. Biomimetic, Smart, and Multivalent Ligands for G-Quadruplex Isolation and Bioorthogonal Imaging. ACS Chemical Biology 2021, 16, 905 -914.

AMA Style

Francesco Rota Sperti, Thibaut Charbonnier, Pauline Lejault, Joanna Zell, Claire Bernhard, Ibai E. Valverde, David Monchaud. Biomimetic, Smart, and Multivalent Ligands for G-Quadruplex Isolation and Bioorthogonal Imaging. ACS Chemical Biology. 2021; 16 (5):905-914.

Chicago/Turabian Style

Francesco Rota Sperti; Thibaut Charbonnier; Pauline Lejault; Joanna Zell; Claire Bernhard; Ibai E. Valverde; David Monchaud. 2021. "Biomimetic, Smart, and Multivalent Ligands for G-Quadruplex Isolation and Bioorthogonal Imaging." ACS Chemical Biology 16, no. 5: 905-914.

Review
Published: 16 February 2021 in Cell Chemical Biology
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Summary For over two decades, the prime objective of the chemical biology community studying G-quadruplexes (G4s) has been to use chemicals to interact with and stabilize G4s in cells to obtain mechanistic interpretations. This strategy has been undoubtedly successful, as demonstrated by recent advances. However, these insights have also led to a fundamental rethinking of G4-targeting strategies: due to the prevalence of G4s in the human genome, transcriptome, and ncRNAome (collectively referred to as the G4ome), and their involvement in human diseases, should we continue developing G4-stabilizing ligands or should we invest in designing molecular tools to unfold G4s? Here, we first focus on how, when, and where G4s fold in cells; then, we describe the enzymatic systems that have evolved to counteract G4 folding and how they have been used as tools to manipulate G4s in cells; finally, we present strategies currently being implemented to devise new molecular G4 unwinding agents.

ACS Style

Pauline Lejault; Jérémie Mitteaux; Francesco Rota Sperti; David Monchaud. How to untie G-quadruplex knots and why? Cell Chemical Biology 2021, 28, 436 -455.

AMA Style

Pauline Lejault, Jérémie Mitteaux, Francesco Rota Sperti, David Monchaud. How to untie G-quadruplex knots and why? Cell Chemical Biology. 2021; 28 (4):436-455.

Chicago/Turabian Style

Pauline Lejault; Jérémie Mitteaux; Francesco Rota Sperti; David Monchaud. 2021. "How to untie G-quadruplex knots and why?" Cell Chemical Biology 28, no. 4: 436-455.

Short communication
Published: 11 February 2021 in Chinese Journal of Catalysis
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The influence of the G-quartet structural integrity on the catalytic activity of the G-quadruplex (G4) was investigated by comparing the G4-DNAzyme performances of a series of G4s with a G-vacancy site and a G-triplex (G-tri). The results presented herein not only confirm that the structural integrity of the 3’-end G-quartet is necessary for G4s to be catalytically competent but also show how to remediate G-vacancy-mediated catalytic activity losses via the addition of guanine surrogates in an approach referred to as G-vacancy complementation strategy that is applicable to parallel G4s only. Furthermore, this study demonstrates that the terminal G-quartet could act as a proximal coordinating group and cooperate with the flanking nucleotide to activate the hemin cofactor.

ACS Style

Jielin Chen; Mingpan Cheng; Jiawei Wang; Dehui Qiu; David Monchaud; Jean-Louis Mergny; Huangxian Ju; Jun Zhou. The catalytic properties of DNA G-quadruplexes rely on their structural integrity. Chinese Journal of Catalysis 2021, 42, 1102 -1107.

AMA Style

Jielin Chen, Mingpan Cheng, Jiawei Wang, Dehui Qiu, David Monchaud, Jean-Louis Mergny, Huangxian Ju, Jun Zhou. The catalytic properties of DNA G-quadruplexes rely on their structural integrity. Chinese Journal of Catalysis. 2021; 42 (7):1102-1107.

Chicago/Turabian Style

Jielin Chen; Mingpan Cheng; Jiawei Wang; Dehui Qiu; David Monchaud; Jean-Louis Mergny; Huangxian Ju; Jun Zhou. 2021. "The catalytic properties of DNA G-quadruplexes rely on their structural integrity." Chinese Journal of Catalysis 42, no. 7: 1102-1107.

Research article
Published: 03 February 2021 in Journal of Chemical Theory and Computation
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Guanine quadruplex nucleic acids (G4s) are involved in key biological processes such as replication or transcription. Beyond their biological relevance, G4s find applications as biotechnological tools since they readily bind hemin and enhance its peroxidase activity, creating a G4-DNAzyme. The biocatalytic properties of G4-DNAzymes have been thoroughly studied and used for biosensing purposes. Despite hundreds of applications and massive experimental efforts, the atomistic details of the reaction mechanism remain unclear. To help select between the different hypotheses currently under investigation, we use extended explicit-solvent molecular dynamics (MD) simulations to scrutinize the G4/hemin interaction. We find that besides the dominant conformation in which hemin is stacked atop the external G-quartets, hemin can also transiently bind to the loops and be brought to the external G-quartets through diverse delivery mechanisms. The simulations do not support the catalytic mechanism relying on a wobbling guanine. Similarly, the catalytic role of the iron-bound water molecule is not in line with our results; however, given the simulation limitations, this observation should be considered with some caution. The simulations rather suggest tentative mechanisms in which the external G-quartet itself could be responsible for the unique H2O2-promoted biocatalytic properties of the G4/hemin complexes. Once stacked atop a terminal G-quartet, hemin rotates about its vertical axis while readily sampling shifted geometries where the iron transiently contacts oxygen atoms of the adjacent G-quartet. This dynamics is not apparent from the ensemble-averaged structure. We also visualize transient interactions between the stacked hemin and the G4 loops. Finally, we investigated interactions between hemin and on-pathway folding intermediates of the parallel-stranded G4 fold. The simulations suggest that hemin drives the folding of parallel-stranded G4s from slip-stranded intermediates, acting as a G4 chaperone. Limitations of the MD technique are briefly discussed.

ACS Style

Petr Stadlbauer; Barira Islam; Michal Otyepka; Jielin Chen; David Monchaud; Jun Zhou; Jean-Louis Mergny; Jiří Šponer. Insights into G-Quadruplex–Hemin Dynamics Using Atomistic Simulations: Implications for Reactivity and Folding. Journal of Chemical Theory and Computation 2021, 17, 1883 -1899.

AMA Style

Petr Stadlbauer, Barira Islam, Michal Otyepka, Jielin Chen, David Monchaud, Jun Zhou, Jean-Louis Mergny, Jiří Šponer. Insights into G-Quadruplex–Hemin Dynamics Using Atomistic Simulations: Implications for Reactivity and Folding. Journal of Chemical Theory and Computation. 2021; 17 (3):1883-1899.

Chicago/Turabian Style

Petr Stadlbauer; Barira Islam; Michal Otyepka; Jielin Chen; David Monchaud; Jun Zhou; Jean-Louis Mergny; Jiří Šponer. 2021. "Insights into G-Quadruplex–Hemin Dynamics Using Atomistic Simulations: Implications for Reactivity and Folding." Journal of Chemical Theory and Computation 17, no. 3: 1883-1899.

Preprint content
Published: 18 December 2020
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G-quadruplexes (G4s) continue to gather wide attention in the field of chemical biology as their prevalence in the human genome and transcriptome strongly suggests that they may play key regulatory roles in cell biology. G4-specific, cell-permeable small molecules (G4-ligands) innovately permit the interrogation of cellular circuitries in order to assess to what extent G4s influence cell fate and functions. Here, we report on multivalent, biomimetic G4-ligands referred to as TASQs that enable both the isolation and visualization of G4s in human cells. Two biotinylated TASQs, BioTASQ and BioCyTASQ, are indeed efficient molecular tools to fish out G4s of mixtures of nucleic acids through simple affinity capture protocols and to image G4s in cells via a biotin/avidin pretargeted imaging system first applied here to G4s, found to be a reliable alternative to in situ click chemistry.

ACS Style

Francesco Rota Sperti; Thibaut Charbonnier; Pauline Lejault; Joanna Zell; Claire Bernhard; Ibai E. Valverde; David Monchaud. Biomimetic, smart and multivalent ligands for G-quadruplex isolation and bioorthogonal imaging. 2020, 1 .

AMA Style

Francesco Rota Sperti, Thibaut Charbonnier, Pauline Lejault, Joanna Zell, Claire Bernhard, Ibai E. Valverde, David Monchaud. Biomimetic, smart and multivalent ligands for G-quadruplex isolation and bioorthogonal imaging. . 2020; ():1.

Chicago/Turabian Style

Francesco Rota Sperti; Thibaut Charbonnier; Pauline Lejault; Joanna Zell; Claire Bernhard; Ibai E. Valverde; David Monchaud. 2020. "Biomimetic, smart and multivalent ligands for G-quadruplex isolation and bioorthogonal imaging." , no. : 1.

Journal article
Published: 27 November 2020 in Molecules
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Age-related macular degeneration (AMD) is a degenerative disease of the retina where the molecular mechanism involves the production of vascular endothelial growth factor (VEGF), a factor of poor prognosis of the progression of the disease. Previous studies have shown that resveratrol, a polyphenol of grapevines, can prevent VEGF secretion induced by stress from retinal cells. Considering the fundamental role played by VEGF in development and progression of AMD, we investigate the potential effect of red wine extract (RWE) on VEGF secretion and its signaling pathway in human retinal cells ARPE-19. To examine the effect of RWE in ARPE-19, a quantitative and qualitative analysis of the RWE was performed by HPLC MS/MS. We show for the first time that RWE decreased VEGF-A secretion from ARPE-19 cells and its protein expression in concentration-dependent manner. RWE-induced alteration in VEGF-A production is associated with a down of VEGF-receptor 2 (VEGF-R2) protein expression and its phosphorylated intracytoplasmic domain. Subsequently, the activation of kinase pathway is disturbing and RWE prevents the phosphorylation of MEK and ERK 1/2 in human retinal cells ARPE-19. Finally, this study sheds light on the interest that the use of polyphenolic cocktails could represent in a prevention strategy.

ACS Style

Clarisse Cornebise; Flavie Courtaut; Marie Taillandier-Coindard; Josep Valls-Fonayet; Tristan Richard; David Monchaud; Virginie Aires; Dominique Delmas. Red Wine Extract Inhibits VEGF Secretion and Its Signaling Pathway in Retinal ARPE-19 Cells to Potentially Disrupt AMD. Molecules 2020, 25, 5564 .

AMA Style

Clarisse Cornebise, Flavie Courtaut, Marie Taillandier-Coindard, Josep Valls-Fonayet, Tristan Richard, David Monchaud, Virginie Aires, Dominique Delmas. Red Wine Extract Inhibits VEGF Secretion and Its Signaling Pathway in Retinal ARPE-19 Cells to Potentially Disrupt AMD. Molecules. 2020; 25 (23):5564.

Chicago/Turabian Style

Clarisse Cornebise; Flavie Courtaut; Marie Taillandier-Coindard; Josep Valls-Fonayet; Tristan Richard; David Monchaud; Virginie Aires; Dominique Delmas. 2020. "Red Wine Extract Inhibits VEGF Secretion and Its Signaling Pathway in Retinal ARPE-19 Cells to Potentially Disrupt AMD." Molecules 25, no. 23: 5564.

Preprint content
Published: 16 November 2020
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The quest for small molecules that avidly bind to G-quadruplex-DNA (G4-DNA, or G4), so called G4-ligands, has invigorated the G4 research field from its very inception. Massive efforts have been invested to i- screen or design G4-ligands, ii- evaluate their G4-interacting properties in vitro through a series of now widely accepted and routinely implemented assays, and iii- use them as unique chemical biology tools to interrogate cellular networks that might involve G4s. In sharp contrast, only uncoordinated efforts at developing small molecules aimed at destabilizing G4s have been invested to date, even though it is now recognized that such molecular tools would have tremendous application to neurobiology as many genetic and age-related diseases are caused by an over-representation of G4s, itself caused by a deficiency of G4-resolving enzymes, the G4-helicases. Herein, we report on our double effort to i- develop a reliable in vitro assay to identify molecules able to destabilize G4s, the G4-unfold assay, and ii- fully characterize the first prototype of G4-disrupting small molecule, a phenylpyrrolcytosine (PhpC)-based G-clamp analog.

ACS Style

Jérémie Mitteaux; Pauline Lejault; Marc Pirrotta; Filip Wojciechowski; Alexandra Joubert; Nicolas Desbois; Claude P. Gros; Robert H. E. Hudson; Jean-Baptiste Boulé; Anton Granzhan; David Monchaud. Disclosing the actual efficiency of G-quadruplex-DNA–disrupting small molecules. 2020, 1 .

AMA Style

Jérémie Mitteaux, Pauline Lejault, Marc Pirrotta, Filip Wojciechowski, Alexandra Joubert, Nicolas Desbois, Claude P. Gros, Robert H. E. Hudson, Jean-Baptiste Boulé, Anton Granzhan, David Monchaud. Disclosing the actual efficiency of G-quadruplex-DNA–disrupting small molecules. . 2020; ():1.

Chicago/Turabian Style

Jérémie Mitteaux; Pauline Lejault; Marc Pirrotta; Filip Wojciechowski; Alexandra Joubert; Nicolas Desbois; Claude P. Gros; Robert H. E. Hudson; Jean-Baptiste Boulé; Anton Granzhan; David Monchaud. 2020. "Disclosing the actual efficiency of G-quadruplex-DNA–disrupting small molecules." , no. : 1.

Preprint content
Published: 10 November 2020
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Guanine quadruplex nucleic acids (G4s) are involved in key biological processes such as replication or transcription. Beyond their biological relevance, G4s find applications as biotechnological tools since they readily bind hemin and enhance its peroxidase activity, creating a G4-DNAzyme. The biocatalytic properties of G4-DNAzymes have been thoroughly studied and used for biosensing purposes. Despite hundreds of applications and massive experimental efforts, the atomistic details of the reaction mechanism remain unclear. To help select between the different hypotheses currently under investigation, we use extended explicit-solvent molecular dynamics (MD) simulations to scrutinize the G4/hemin interaction. We find that besides the dominant conformation in which hemin is stacked atop the external G-quartets, hemin can also transiently bind to the loops and be brought to the external G-quartets through diverse delivery mechanisms. The simulations do not support the catalytic mechanism relying on a wobbling guanine. Similarly, catalytic role of the iron-bound water molecule is not in line with our results, however, given the simulation limitations, this observation should be considered with some caution. The simulations rather suggest tentative mechanisms in which the external G-quartet itself could be responsible for the unique H2O2-promoted biocatalytic properties of the G4/hemin complexes. Once stacked atop a terminal G-quartet, hemin rotates about its vertical axis while readily sampling shifted geometries where the iron transiently contacts oxygen atoms of the adjacent G-quartet. This dynamics is not apparent from the ensemble-averaged structure. We also visualize transient interactions between the stacked hemin and the G4 loops. Finally, we investigated interactions between hemin and on-pathway folding intermediates of the parallel-stranded G4 fold. The simulations suggest that hemin drives the folding of parallel-stranded G4s from slip-stranded intermediates, acting as a G4 chaperone. Limitations of the MD technique are briefly discussed.For Table of Contents Only

ACS Style

Petr Stadlbauer; Barira Islam; Michal Otyepka; Jielin Chen; David Monchaud; Jun Zhou; Jean-Louis Mergny; Jiří Šponer. Insights into G-Quadruplex–Hemin Dynamics Using Atomistic Simulations: Implications for Reactivity and Folding. 2020, 1 .

AMA Style

Petr Stadlbauer, Barira Islam, Michal Otyepka, Jielin Chen, David Monchaud, Jun Zhou, Jean-Louis Mergny, Jiří Šponer. Insights into G-Quadruplex–Hemin Dynamics Using Atomistic Simulations: Implications for Reactivity and Folding. . 2020; ():1.

Chicago/Turabian Style

Petr Stadlbauer; Barira Islam; Michal Otyepka; Jielin Chen; David Monchaud; Jun Zhou; Jean-Louis Mergny; Jiří Šponer. 2020. "Insights into G-Quadruplex–Hemin Dynamics Using Atomistic Simulations: Implications for Reactivity and Folding." , no. : 1.

Review article
Published: 30 September 2020 in RSC Chemical Biology
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Alternative DNA structures (including G-quadruplexes and DNA junctions) represent promising targets for combinatorial chemotherapeutic treatments aiming at fostering genomic instability and impeding DNA repair.

ACS Style

Joanna Zell; Francesco Rota Sperti; Sébastien Britton; David Monchaud. DNA folds threaten genetic stability and can be leveraged for chemotherapy. RSC Chemical Biology 2020, 2, 47 -76.

AMA Style

Joanna Zell, Francesco Rota Sperti, Sébastien Britton, David Monchaud. DNA folds threaten genetic stability and can be leveraged for chemotherapy. RSC Chemical Biology. 2020; 2 (1):47-76.

Chicago/Turabian Style

Joanna Zell; Francesco Rota Sperti; Sébastien Britton; David Monchaud. 2020. "DNA folds threaten genetic stability and can be leveraged for chemotherapy." RSC Chemical Biology 2, no. 1: 47-76.

Edge article
Published: 12 August 2020 in Chemical Science
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Cofactor hemin is sandwiched between 3′ homodimeric G-quadruplexes, leading to an excellent DNAzyme as a mimic of peroxidase and monooxygenase.

ACS Style

Yu Cheng; Mingpan Cheng; Jingya Hao; Guoqing Jia; David Monchaud; Can Li. The noncovalent dimerization of a G-quadruplex/hemin DNAzyme improves its biocatalytic properties. Chemical Science 2020, 11, 8846 -8853.

AMA Style

Yu Cheng, Mingpan Cheng, Jingya Hao, Guoqing Jia, David Monchaud, Can Li. The noncovalent dimerization of a G-quadruplex/hemin DNAzyme improves its biocatalytic properties. Chemical Science. 2020; 11 (33):8846-8853.

Chicago/Turabian Style

Yu Cheng; Mingpan Cheng; Jingya Hao; Guoqing Jia; David Monchaud; Can Li. 2020. "The noncovalent dimerization of a G-quadruplex/hemin DNAzyme improves its biocatalytic properties." Chemical Science 11, no. 33: 8846-8853.

Addendum
Published: 10 June 2020 in Autophagy
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Guanine-rich DNA strands can form secondary structures known as G-quadruplexes (G4-DNA). G4-DNA is important for the regulation of replication and transcription. We recently showed that the expression of Atg7, a gene that is critical for macroautophagy/autophagy, is controlled by G4-DNA in neurons. We demonstrated that the transcription factor SUB1/PC4 and the G4-DNA-specific antibody HF2 bind to a putative G4-DNA motif located in the Atg7 gene. Stabilizing G4-DNA with the G4-ligand pyridostatin (PDS) downregulates Atg7 expression in neurons. Here, we further investigated how G4-DNA in the Atg7 gene is stabilized by PDS. We show that PDS can form 1:1 and 2:1 complexes with the Atg7’s G4. We also demonstrate that PDS downregulates the ATG7 protein and the expression of Atg7 in astrocytes as well as in neurons. Together with our previous findings, these data establish a novel G4-DNA-associated mechanism of autophagy regulation at a transcriptional level in neurons and astrocytes.

ACS Style

Pauline Lejault; Jose F. Moruno-Manchon; Sree M. Vemu; Pedram Honarpisheh; Liang Zhu; Nayun Kim; Akihiko Urayama; David Monchaud; Louise Mccullough; Andrey S. Tsvetkov. Regulation of autophagy by DNA G-quadruplexes. Autophagy 2020, 16, 2252 -2259.

AMA Style

Pauline Lejault, Jose F. Moruno-Manchon, Sree M. Vemu, Pedram Honarpisheh, Liang Zhu, Nayun Kim, Akihiko Urayama, David Monchaud, Louise Mccullough, Andrey S. Tsvetkov. Regulation of autophagy by DNA G-quadruplexes. Autophagy. 2020; 16 (12):2252-2259.

Chicago/Turabian Style

Pauline Lejault; Jose F. Moruno-Manchon; Sree M. Vemu; Pedram Honarpisheh; Liang Zhu; Nayun Kim; Akihiko Urayama; David Monchaud; Louise Mccullough; Andrey S. Tsvetkov. 2020. "Regulation of autophagy by DNA G-quadruplexes." Autophagy 16, no. 12: 2252-2259.

Book chapter
Published: 28 May 2020 in Annual Reports in Medicinal Chemistry
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The precise detection of both DNA and RNA quadruplexes in human cells remains challenging. Efforts are being invested to design, synthesize and operate molecular tools to track and detect quadruplexes in cells. Such probes now have sufficient molecular specificity and suitable spectroscopic properties to shed light on quadruplexes in their cellular context, thus providing reliable details about their existence in cells. Herein, the most important steps in this line of development are summarized, from the very first attempts with organometallic complexes to the development of immunodetection technologies; and from in vitro to live-cell investigations performed with cell-permeable quadruplex-specific small molecule dyes. The results obtained with the most recent molecular systems are also compared, highlighting how fine-tuned fluorescent probes (structure optimization, fluorescence responsiveness, etc.) provide unique insights into the prevalence and relevance of quadruplex landscapes in human cells.

ACS Style

David Monchaud. Quadruplex detection in human cells. Annual Reports in Medicinal Chemistry 2020, 133 -160.

AMA Style

David Monchaud. Quadruplex detection in human cells. Annual Reports in Medicinal Chemistry. 2020; ():133-160.

Chicago/Turabian Style

David Monchaud. 2020. "Quadruplex detection in human cells." Annual Reports in Medicinal Chemistry , no. : 133-160.

Journal article
Published: 11 February 2020 in eLife
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Guanine-rich DNA sequences can fold into four-stranded G-quadruplex (G4-DNA) structures. G4-DNA regulates replication and transcription, at least in cancer cells. Here, we demonstrate that, in neurons, pharmacologically stabilizing G4-DNA with G4 ligands strongly downregulates the Atg7 gene. Atg7 is a critical gene for the initiation of autophagy that exhibits decreased transcription with aging. Using an in vitro assay, we show that a putative G-quadruplex-forming sequence (PQFS) in the first intron of the Atg7 gene folds into a G4. An antibody specific to G4-DNA and the G4-DNA-binding protein PC4 bind to the Atg7 PQFS. Mice treated with a G4 stabilizer develop memory deficits. Brain samples from aged mice contain G4-DNA structures that are absent in brain samples from young mice. Overexpressing the G4-DNA helicase Pif1 in neurons exposed to the G4 stabilizer improves phenotypes associated with G4-DNA stabilization. Our findings indicate that G4-DNA is a novel pathway for regulating autophagy in neurons.

ACS Style

Jose F Moruno-Manchon; Pauline Lejault; Yaoxuan Wang; Brenna McCauley; Pedram Honarpisheh; Diego A Morales Scheihing; Shivani Singh; Weiwei Dang; Nayun Kim; Akihiko Urayama; Liang Zhu; David Monchaud; Louise D McCullough; Andrey S Tsvetkov. Small-molecule G-quadruplex stabilizers reveal a novel pathway of autophagy regulation in neurons. eLife 2020, 9, 1 .

AMA Style

Jose F Moruno-Manchon, Pauline Lejault, Yaoxuan Wang, Brenna McCauley, Pedram Honarpisheh, Diego A Morales Scheihing, Shivani Singh, Weiwei Dang, Nayun Kim, Akihiko Urayama, Liang Zhu, David Monchaud, Louise D McCullough, Andrey S Tsvetkov. Small-molecule G-quadruplex stabilizers reveal a novel pathway of autophagy regulation in neurons. eLife. 2020; 9 ():1.

Chicago/Turabian Style

Jose F Moruno-Manchon; Pauline Lejault; Yaoxuan Wang; Brenna McCauley; Pedram Honarpisheh; Diego A Morales Scheihing; Shivani Singh; Weiwei Dang; Nayun Kim; Akihiko Urayama; Liang Zhu; David Monchaud; Louise D McCullough; Andrey S Tsvetkov. 2020. "Small-molecule G-quadruplex stabilizers reveal a novel pathway of autophagy regulation in neurons." eLife 9, no. : 1.

Journals
Published: 07 January 2020 in Chemical Communications
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Oxidative damage of guanine to 8-oxoguanine triggers a partial and variable loss of G-quadruplex/hemin DNAzyme activity and provides clues to the mechanistic origins of DNAzyme deactivation.

ACS Style

Jiawei Wang; Mingpan Cheng; Jielin Chen; Huangxian Ju; David Monchaud; Jean-Louis Mergny; Jun Zhou. An oxidatively damaged G-quadruplex/hemin DNAzyme. Chemical Communications 2020, 56, 1839 -1842.

AMA Style

Jiawei Wang, Mingpan Cheng, Jielin Chen, Huangxian Ju, David Monchaud, Jean-Louis Mergny, Jun Zhou. An oxidatively damaged G-quadruplex/hemin DNAzyme. Chemical Communications. 2020; 56 (12):1839-1842.

Chicago/Turabian Style

Jiawei Wang; Mingpan Cheng; Jielin Chen; Huangxian Ju; David Monchaud; Jean-Louis Mergny; Jun Zhou. 2020. "An oxidatively damaged G-quadruplex/hemin DNAzyme." Chemical Communications 56, no. 12: 1839-1842.

Research article
Published: 13 December 2019 in Journal of the American Chemical Society
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Translocation of DNA and RNA polymerases along their duplex substrates results in DNA supercoiling. This torsional stress promotes the formation of plectonemic structures, including three-way DNA junction (TWJ), which can block DNA transactions and lead to DNA damage. While cells have evolved multiple mechanisms to prevent the accumulation of such structures, stabilizing TWJ through ad hoc ligands offer an opportunity to trigger DNA damage in cells with high level of transcription and replication, such as cancer cells. Here, we develop a series of azacryptand-based TWJ ligands, we thoroughly characterize their TWJ-interacting properties in vitro and demonstrate their capacity to trigger DNA damage in rapidly dividing human cancer cells. We also demonstrate that TWJ ligands are amenable to chemically induced synthetic lethality strategies upon association with inhibitors of DNA repair, thus paving the way towards innovative drug combinations to fight cancers.

ACS Style

Katerina Duskova; Pauline Lejault; Élie Benchimol; Régis Guillot; Sébastien Britton; Anton Granzhan; David Monchaud. DNA Junction Ligands Trigger DNA Damage and Are Synthetic Lethal with DNA Repair Inhibitors in Cancer Cells. Journal of the American Chemical Society 2019, 142, 424 -435.

AMA Style

Katerina Duskova, Pauline Lejault, Élie Benchimol, Régis Guillot, Sébastien Britton, Anton Granzhan, David Monchaud. DNA Junction Ligands Trigger DNA Damage and Are Synthetic Lethal with DNA Repair Inhibitors in Cancer Cells. Journal of the American Chemical Society. 2019; 142 (1):424-435.

Chicago/Turabian Style

Katerina Duskova; Pauline Lejault; Élie Benchimol; Régis Guillot; Sébastien Britton; Anton Granzhan; David Monchaud. 2019. "DNA Junction Ligands Trigger DNA Damage and Are Synthetic Lethal with DNA Repair Inhibitors in Cancer Cells." Journal of the American Chemical Society 142, no. 1: 424-435.

Journal article
Published: 17 November 2019 in International Journal of Biological Macromolecules
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Here we report on the design of a new catalytic G-quadruplex-DNA system (G4-DNAzyme) based on the modification of the DNA scaffold to provide the DNA pre-catalyst with two identical 3′-ends, known to be more catalytically proficient than the 5′-ends. To this end, we introduced a 5′-5′ inversion of polarity site in the middle of the G4-forming sequences AG4A and AG6A to obtain d(3′AGG5′-5′GGA3′) (or AG2-G2A) and d(3′AGGG5′-5′GGGA3′) (or AG3-G3A) that fold into stable G4 whose tetramolecular nature was confirmed via nuclear magnetic resonance (NMR) and circular dichroism (CD) investigations. Both AG2-G2A and AG3-G3A display two identical external G-quartets (3′-ends) known to interact with the cofactor hemin with a high efficiency, making the resulting complex competent to perform hemoprotein-like catalysis (G4-DNAzyme). A systematic comparison of the performances of modified and unmodified G4s lends credence to the relevance of the modification exploited here (5′-5′ inversion of polarity site), which represents a new chemical opportunity to improve the overall activity of catalytic G4s.

ACS Style

Antonella Virgilio; Veronica Esposito; Pauline Lejault; David Monchaud; Aldo Galeone. Improved performances of catalytic G-quadruplexes (G4-DNAzymes) via the chemical modifications of the DNA backbone to provide G-quadruplexes with double 3′-external G-quartets. International Journal of Biological Macromolecules 2019, 151, 976 -983.

AMA Style

Antonella Virgilio, Veronica Esposito, Pauline Lejault, David Monchaud, Aldo Galeone. Improved performances of catalytic G-quadruplexes (G4-DNAzymes) via the chemical modifications of the DNA backbone to provide G-quadruplexes with double 3′-external G-quartets. International Journal of Biological Macromolecules. 2019; 151 ():976-983.

Chicago/Turabian Style

Antonella Virgilio; Veronica Esposito; Pauline Lejault; David Monchaud; Aldo Galeone. 2019. "Improved performances of catalytic G-quadruplexes (G4-DNAzymes) via the chemical modifications of the DNA backbone to provide G-quadruplexes with double 3′-external G-quartets." International Journal of Biological Macromolecules 151, no. : 976-983.