Jean-louis Mergny - Academia.edu (original) (raw)

Papers by Jean-louis Mergny

Scientific reports, 2015

Telomeres are nucleoprotein structures at the end of chromosomes which stabilize and protect them... more Telomeres are nucleoprotein structures at the end of chromosomes which stabilize and protect them from nucleotidic degradation and end-to-end fusions. The G-rich telomeric single-stranded DNA overhang can adopt a four-stranded G-quadruplex DNA structure (G4). Stabilization of the G4 structure by binding of small molecule ligands enhances radiosensitivity of tumor cells, and this combined treatment represents a novel anticancer approach. We studied the effect of the platinum-derived G4-ligand, Pt-ctpy, in association with radiation on human glioblastoma (SF763 and SF767) and non-small cell lung cancer (A549 and H1299) cells in vitro and in vivo. Treatments with submicromolar concentrations of Pt-ctpy inhibited tumor proliferation in vitro with cell cycle alterations and induction of apoptosis. Non-toxic concentrations of the ligand were then combined with ionizing radiation. Pt-ctpy radiosensitized all cell lines with dose-enhancement factors between 1.32 and 1.77. The combined treat...

Biochimie, 2015

The equilibrium between G-quadruplex (G4) and duplex DNA structures is a fundamental question whe... more The equilibrium between G-quadruplex (G4) and duplex DNA structures is a fundamental question whenever G4 are considered within a genomic context. In this study, we performed a detailed thermodynamic and kinetic analysis of this equilibria using a new fast and high throughput technique for the screening of G4 structures. This assay examines the isothermal stability of G-quadruplexes in the presence of complementary strands monitoring the unwinding process by fluorescence techniques. Unlabelled G4 structures were used in order to avoid any thermodynamic effect that fluorophores could have on the G4 stability. The assay was applied to investigate the effect that flanking sequences can have on the thermodynamic stability of the quadruplex motifs. Interestingly, the presence of adjacent bases to the G4 structure facilitates the recognition of the complementary strand accelerating the G4 unfolding reaction. The simplicity of the systems employed and the use of fluorescence emission allowed the use of high throughput techniques and to monitor the opening reaction in real time in a "pseudo" label-free method. This G4 opening reaction may be easily implemented as a new isothermal assay for the screening of G4 structures, G4 ligands or G4-binding proteins.

Nucleic acids research, Jan 29, 2014

In recent years, an increasing number of reports have been focused on the structure and biologica... more In recent years, an increasing number of reports have been focused on the structure and biological role of non-canonical nucleic acid secondary structures. Many of these studies involve the use of oligonucleotides that can often adopt a variety of structures depending on the experimental conditions, and hence change the outcome of an assay. The knowledge of the structure(s) formed by oligonucleotides is thus critical to correctly interpret the results, and gain insight into the biological role of these particular sequences. Herein we demonstrate that size-exclusion HPLC (SE-HPLC) is a simple yet surprisingly powerful tool to quickly and effortlessly assess the secondary structure(s) formed by oligonucleotides. For the first time, an extensive calibration and validation of the use of SE-HPLC to confidently detect the presence of different species displaying various structure and/or molecularity, involving >110 oligonucleotides forming a variety of secondary structures (antiparalle...

Journal of Chemical Information and Modeling, 2015

Telomeres and telomerase are key players in tumorogenesis. Among the various strategies proposed ... more Telomeres and telomerase are key players in tumorogenesis. Among the various strategies proposed for telomerase inhibition or telomere uncapping, the stabilization of telomeric G-quadruplex (G4) structures is a very promising one. Additionally, G4 stabilizing ligands also act over tumors mediated by the alternative elongation of telomeres. Accordingly, the discovery of novel compounds able to act on telomeres and/or inhibit the telomerase enzyme by stabilizing DNA telomeric G4 structures, as well as the development of approaches efficiently prioritizing such compounds constitute active areas of research in computational medicinal chemistry and anti-cancer drug discovery. In this direction, we applied a virtual screening strategy based on the rigorous application of QSAR best practices and its harmonized integration with structure-based methods. More than 600,000 compounds from commercial databases were screened, the first 99 compounds were prioritized, and 21 commercially available and structurally diverse candidates were purchased and submitted to experimental assays. Such strategy proved to be highly efficient in the prioritization of G4 stabilizer hits, with a hit rate of 23.5%. The best G4 stabilizer hit found exhibited a shift in melting temperature from FRET assay of +7.3 °C at 5 µM, while other three candidates also exhibited a promising stabilizing profile. The two most promising candidates also exhibited a good telomerase inhibitory ability and a mild inhibition of HeLa cells growth. None of these candidates showed anti-proliferative effects in normal fibroblasts. Finally, the proposed virtual screening strategy proved to be a practical and reliable tool for the discovery of novel G4 ligands which can be used as starting points of further optimization campaigns.

Carcinogenesis, 2014

Germline TP53 mutations predispose to multiple cancers defining Li-Fraumeni/Li-Fraumeni-like synd... more Germline TP53 mutations predispose to multiple cancers defining Li-Fraumeni/Li-Fraumeni-like syndrome (LFS/LFL), a disease with large individual disparities in cancer profiles and age of onset. G-quadruplexes (G4s) are secondary structural motifs occurring in guanine tracks, with regulatory effects on DNA and RNA. We analyzed 85 polymorphisms within or near five predicted G4s in TP53 in search of modifiers of penetrance of LFS/LFL in Brazilian cancer families with (n = 35) or without (n = 110) TP53 mutations. Statistical analyses stratified on family structure showed that cancer tended to occur ~15 years later in mutation carriers who also carried the variant alleles of two polymorphisms within predicted G4-forming regions, rs17878362 (TP53 PIN3, 16 bp duplication in intron 3; P = 0.082) and rs17880560 (6 bp duplication in 3′ flanking region; P = 0.067). Haplotype analysis showed that this inverse association was driven by the polymorphic status of the remaining wild-type (WT) haplotype in mutation carriers: in carriers with a WT haplotype containing at least one variant allele of rs17878362 or rs17880560, cancer occurred ~15 years later than in carriers with other WT haplotypes (P = 0.019). No effect on age of cancer onset was observed in subjects without a TP53 mutation. The G4 in intron 3 has been shown to regulate alternative p53 messenger RNA splicing, whereas the biological roles of predicted G4s in the 3′ flanking region remain to be elucidated. In conclusion, this study demonstrates that G4 polymorphisms in haplotypes of the WT TP53 allele have an impact on LFS/LFL penetrance in germline TP53 mutation carriers.

Nucleic acids research, Jan 12, 2015

Helicases, enzymes that unwind DNA or RNA structure, are present in the cell nucleus and in the m... more Helicases, enzymes that unwind DNA or RNA structure, are present in the cell nucleus and in the mitochondrion. Although the majority of the helicases unwind DNA or RNA duplexes, some of these proteins are known to resolve unusual structures such as G-quadruplexes (G4) in vitro. G4 may form stable barrier to the progression of molecular motors tracking on DNA. Monitoring G4 unwinding by these enzymes may reveal the mechanisms of the enzymes and provides information about the stability of these structures. In the experiments presented herein, we developed a reliable, inexpensive and rapid fluorescence-based technique to monitor the activity of G4 helicases in real time in a 96-well plate format. This system was used to screen a series of G4 structures and G4 binders for their effect on the Pif1 enzyme, a 5' to 3' DNA helicase. This simple assay should be adaptable to analysis of other helicases and G4 structures.

Macrocyclic scaffolds are particularly attractive for designing selective G-quadruplex ligands es... more Macrocyclic scaffolds are particularly attractive for designing selective G-quadruplex ligands essentially because, on one hand, they show a poor affinity for the "standard" B-DNA conformation and, on the other hand, they fit nicely with the external G-quartets of quadruplexes. Stimulated by the pioneering studies on the cationic porphyrin TMPyP4 and the natural product telomestatin, follow-up studies have developed, rapidly leading to a large diversity of macrocyclic structures with remarkablequadruplex binding properties and biological activities. In this review we summarize the current state of the art in detailing the three main categories of quadruplex-binding macrocycles described so far (telomestatin-like polyheteroarenes, porphyrins and derivatives, polyammonium cyclophanes), and in addressing both synthetic issues and biological aspects.

Macrocyclic scaffolds are particularly attractive for designing selective G-quadruplex ligands es... more Macrocyclic scaffolds are particularly attractive for designing selective G-quadruplex ligands essentially because, on one hand, they show a poor affinity for the "standard" B-DNA conformation and, on the other hand, they fit nicely with the external G-quartets of quadruplexes. Stimulated by the pioneering studies on the cationic porphyrin TMPyP4 and the natural product telomestatin, follow-up studies have developed, rapidly leading to a large diversity of macrocyclic structures with remarkablequadruplex binding properties and biological activities. In this review we summarize the current state of the art in detailing the three main categories of quadruplex-binding macrocycles described so far (telomestatin-like polyheteroarenes, porphyrins and derivatives, polyammonium cyclophanes), and in addressing both synthetic issues and biological aspects.

Current Protocols in Nucleic Acid Chemistry, 2001

ABSTRACT Absorbance versus temperature curves can provide information on the thermal stability of... more ABSTRACT Absorbance versus temperature curves can provide information on the thermal stability of DNA or RNA quadruplexes. Quadruplex denaturation or renaturation can be followed by recording absorbance at 295 nm rather than 260 nm, the wavelength used to monitor duplex denaturation. This unit describes the use of absorbance versus temperature curves to determine melting temperatures (T(m) values) and model-dependent thermodynamic parameters.

A collection of 26 polyammonium cyclophane-type macrocycles with a large structural diversity has... more A collection of 26 polyammonium cyclophane-type macrocycles with a large structural diversity has been screened for Gquadruplex recognition. A two-step selection procedure based on the FRET-melting assay was carried out enabling identification of macrocycles of high affinity (ΔT 1/2 up to 30 • C) and high selectivity for the human telomeric G-quadruplex. The four selected hits possess sophisticated architectures, more particularly the presence of a pendant side-arm as well as the existence of a particular topological arrangement appear to be strong determinants of quadruplex binding. These compounds are thus likely to create multiple contacts with the target that may be at the origin of their high selectivity, thereby suggesting that this class of macrocycles offers unique advantages for targeting G-quadruplex-DNA.

ChemInform, 2007

ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Chemical Science, 2013

ABSTRACT The effects of modification of the phosphodiester backbone or the guanine bases on G-qua... more ABSTRACT The effects of modification of the phosphodiester backbone or the guanine bases on G-quadruplex formation have been widely investigated. Only a few studies have investigated the effects of deoxyribose or ‘sugar’ modifications on G-quadruplex structure. Here, we evaluated the structural, thermodynamic, and kinetic properties of the parallel quadruplexes formed by the sequence d(TGGGGT) in which each guanine base was substituted, one at a time, with acyclic threoninol nucleic acid (aTNA). We found that all sequences were able to form G-quadruplexes; however, the presence of aTNA resulted in the formation of a mixture of quadruplex structures in some cases. Furthermore, the presence of a single substitution at any position resulted in destabilization of the G-quadruplex relative to that formed by the unmodified sequence. The introduction of the aTNA in terminal quartets was the most detrimental to stability. In addition, kinetic experiments showed that, compared to its unmodified counterpart sequence d(TGGGGT), the substitution of a normal guanine nucleotide by aTNA decelerated quadruplex formation except when the aTNA was at the 5′ most guanine of the sequence. In summary, our studies indicate that the deoxyribose sugar affects the properties of G-quadruplex structures.

Journal of Nucleic Acids, 2010

G-quadruplexes are a family of four-stranded structures stabilized by guanine quartets, in which ... more G-quadruplexes are a family of four-stranded structures stabilized by guanine quartets, in which four planar guanines establish a cyclic array of hydrogen bonds. They are of special interest due to the increasing evidence for their formation in vivo and their possible implication in biology, especially at telomeres and as contributors to gene regulation. Moreover, G-quadruplexes are also formed as a result of self-assembling processes of guanosine derivatives, yielding several interesting motifs such as G-ribbons and G-wires which have peculiar electrical conductivity properties that are being explored as molecular wires.

Journal of Nucleic Acids, 2010

G-quadruplexes are a family of four-stranded structures stabilized by guanine quartets, in which ... more G-quadruplexes are a family of four-stranded structures stabilized by guanine quartets, in which four planar guanines establish a cyclic array of hydrogen bonds. They are of special interest due to the increasing evidence for their formation in vivo and their possible implication in biology, especially at telomeres and as contributors to gene regulation. Moreover, G-quadruplexes are also formed as a result of self-assembling processes of guanosine derivatives, yielding several interesting motifs such as G-ribbons and G-wires which have peculiar electrical conductivity properties that are being explored as molecular wires.

Topics in Current Chemistry, 2012

Guanine quadruplexes (G4) are unusual four-stranded nucleic acid structures formed by G-rich DNA/... more Guanine quadruplexes (G4) are unusual four-stranded nucleic acid structures formed by G-rich DNA/RNA. Beyond their likely biological relevance, the self-assembly, stability, and rigidity of these structures are also interesting for nanotechnology and biotechnology applications. Therefore, efforts are carried out to understand the rules that govern stability and folding of G-quadruplexes. We focus this chapter on tetramolecular conformations which are simple tractable models. We report here the experimental parameters, molecules, and modifications that affect thermal stability and/or association kinetics of these structures. Some chemical modifications which facilitate tetramolecular quadruplex formation and can be useful for nano-or biotechnology are also described.

Proceedings of the National Academy of Sciences, 2003

There is currently great interest in the design of nanodevices that are capable of performing lin... more There is currently great interest in the design of nanodevices that are capable of performing linear or rotary movements. Protein molecular machines are abundant in biology but it has recently been proposed that nucleic acids could also act as nanomolecular machines in model systems. Several types of movements have been described with DNA machines: rotation and "scissors-like" opening and closing. Here we show a nanomachine that is capable of an extension-contraction movement. The simple and robust device described here is composed of a single 21-base oligonucleotide and relies on a duplex-quadruplex equilibrium that may be fueled by the sequential addition of DNA single strands, generating a DNA duplex as a by-product. The interconversion between two well defined topological states induces a 5-nm two-stroke, linear motor-type movement, which is detected by fluorescence resonance energy transfer spectroscopy.

Proceedings of the National Academy of Sciences, 2001

Abbreviations: FRET, fluorescence resonance energy transfer; G4-DNA, quadruplex DNA based on guan... more Abbreviations: FRET, fluorescence resonance energy transfer; G4-DNA, quadruplex DNA based on guanine quartets; TRAP, telomerase repeat amplification protocol. † To whom reprint requests should be addressed.

Scientific reports, 2015

Telomeres are nucleoprotein structures at the end of chromosomes which stabilize and protect them... more Telomeres are nucleoprotein structures at the end of chromosomes which stabilize and protect them from nucleotidic degradation and end-to-end fusions. The G-rich telomeric single-stranded DNA overhang can adopt a four-stranded G-quadruplex DNA structure (G4). Stabilization of the G4 structure by binding of small molecule ligands enhances radiosensitivity of tumor cells, and this combined treatment represents a novel anticancer approach. We studied the effect of the platinum-derived G4-ligand, Pt-ctpy, in association with radiation on human glioblastoma (SF763 and SF767) and non-small cell lung cancer (A549 and H1299) cells in vitro and in vivo. Treatments with submicromolar concentrations of Pt-ctpy inhibited tumor proliferation in vitro with cell cycle alterations and induction of apoptosis. Non-toxic concentrations of the ligand were then combined with ionizing radiation. Pt-ctpy radiosensitized all cell lines with dose-enhancement factors between 1.32 and 1.77. The combined treat...

Biochimie, 2015

The equilibrium between G-quadruplex (G4) and duplex DNA structures is a fundamental question whe... more The equilibrium between G-quadruplex (G4) and duplex DNA structures is a fundamental question whenever G4 are considered within a genomic context. In this study, we performed a detailed thermodynamic and kinetic analysis of this equilibria using a new fast and high throughput technique for the screening of G4 structures. This assay examines the isothermal stability of G-quadruplexes in the presence of complementary strands monitoring the unwinding process by fluorescence techniques. Unlabelled G4 structures were used in order to avoid any thermodynamic effect that fluorophores could have on the G4 stability. The assay was applied to investigate the effect that flanking sequences can have on the thermodynamic stability of the quadruplex motifs. Interestingly, the presence of adjacent bases to the G4 structure facilitates the recognition of the complementary strand accelerating the G4 unfolding reaction. The simplicity of the systems employed and the use of fluorescence emission allowed the use of high throughput techniques and to monitor the opening reaction in real time in a "pseudo" label-free method. This G4 opening reaction may be easily implemented as a new isothermal assay for the screening of G4 structures, G4 ligands or G4-binding proteins.

Nucleic acids research, Jan 29, 2014

In recent years, an increasing number of reports have been focused on the structure and biologica... more In recent years, an increasing number of reports have been focused on the structure and biological role of non-canonical nucleic acid secondary structures. Many of these studies involve the use of oligonucleotides that can often adopt a variety of structures depending on the experimental conditions, and hence change the outcome of an assay. The knowledge of the structure(s) formed by oligonucleotides is thus critical to correctly interpret the results, and gain insight into the biological role of these particular sequences. Herein we demonstrate that size-exclusion HPLC (SE-HPLC) is a simple yet surprisingly powerful tool to quickly and effortlessly assess the secondary structure(s) formed by oligonucleotides. For the first time, an extensive calibration and validation of the use of SE-HPLC to confidently detect the presence of different species displaying various structure and/or molecularity, involving >110 oligonucleotides forming a variety of secondary structures (antiparalle...

Journal of Chemical Information and Modeling, 2015

Telomeres and telomerase are key players in tumorogenesis. Among the various strategies proposed ... more Telomeres and telomerase are key players in tumorogenesis. Among the various strategies proposed for telomerase inhibition or telomere uncapping, the stabilization of telomeric G-quadruplex (G4) structures is a very promising one. Additionally, G4 stabilizing ligands also act over tumors mediated by the alternative elongation of telomeres. Accordingly, the discovery of novel compounds able to act on telomeres and/or inhibit the telomerase enzyme by stabilizing DNA telomeric G4 structures, as well as the development of approaches efficiently prioritizing such compounds constitute active areas of research in computational medicinal chemistry and anti-cancer drug discovery. In this direction, we applied a virtual screening strategy based on the rigorous application of QSAR best practices and its harmonized integration with structure-based methods. More than 600,000 compounds from commercial databases were screened, the first 99 compounds were prioritized, and 21 commercially available and structurally diverse candidates were purchased and submitted to experimental assays. Such strategy proved to be highly efficient in the prioritization of G4 stabilizer hits, with a hit rate of 23.5%. The best G4 stabilizer hit found exhibited a shift in melting temperature from FRET assay of +7.3 °C at 5 µM, while other three candidates also exhibited a promising stabilizing profile. The two most promising candidates also exhibited a good telomerase inhibitory ability and a mild inhibition of HeLa cells growth. None of these candidates showed anti-proliferative effects in normal fibroblasts. Finally, the proposed virtual screening strategy proved to be a practical and reliable tool for the discovery of novel G4 ligands which can be used as starting points of further optimization campaigns.

Carcinogenesis, 2014

Germline TP53 mutations predispose to multiple cancers defining Li-Fraumeni/Li-Fraumeni-like synd... more Germline TP53 mutations predispose to multiple cancers defining Li-Fraumeni/Li-Fraumeni-like syndrome (LFS/LFL), a disease with large individual disparities in cancer profiles and age of onset. G-quadruplexes (G4s) are secondary structural motifs occurring in guanine tracks, with regulatory effects on DNA and RNA. We analyzed 85 polymorphisms within or near five predicted G4s in TP53 in search of modifiers of penetrance of LFS/LFL in Brazilian cancer families with (n = 35) or without (n = 110) TP53 mutations. Statistical analyses stratified on family structure showed that cancer tended to occur ~15 years later in mutation carriers who also carried the variant alleles of two polymorphisms within predicted G4-forming regions, rs17878362 (TP53 PIN3, 16 bp duplication in intron 3; P = 0.082) and rs17880560 (6 bp duplication in 3′ flanking region; P = 0.067). Haplotype analysis showed that this inverse association was driven by the polymorphic status of the remaining wild-type (WT) haplotype in mutation carriers: in carriers with a WT haplotype containing at least one variant allele of rs17878362 or rs17880560, cancer occurred ~15 years later than in carriers with other WT haplotypes (P = 0.019). No effect on age of cancer onset was observed in subjects without a TP53 mutation. The G4 in intron 3 has been shown to regulate alternative p53 messenger RNA splicing, whereas the biological roles of predicted G4s in the 3′ flanking region remain to be elucidated. In conclusion, this study demonstrates that G4 polymorphisms in haplotypes of the WT TP53 allele have an impact on LFS/LFL penetrance in germline TP53 mutation carriers.

Nucleic acids research, Jan 12, 2015

Helicases, enzymes that unwind DNA or RNA structure, are present in the cell nucleus and in the m... more Helicases, enzymes that unwind DNA or RNA structure, are present in the cell nucleus and in the mitochondrion. Although the majority of the helicases unwind DNA or RNA duplexes, some of these proteins are known to resolve unusual structures such as G-quadruplexes (G4) in vitro. G4 may form stable barrier to the progression of molecular motors tracking on DNA. Monitoring G4 unwinding by these enzymes may reveal the mechanisms of the enzymes and provides information about the stability of these structures. In the experiments presented herein, we developed a reliable, inexpensive and rapid fluorescence-based technique to monitor the activity of G4 helicases in real time in a 96-well plate format. This system was used to screen a series of G4 structures and G4 binders for their effect on the Pif1 enzyme, a 5' to 3' DNA helicase. This simple assay should be adaptable to analysis of other helicases and G4 structures.

Macrocyclic scaffolds are particularly attractive for designing selective G-quadruplex ligands es... more Macrocyclic scaffolds are particularly attractive for designing selective G-quadruplex ligands essentially because, on one hand, they show a poor affinity for the "standard" B-DNA conformation and, on the other hand, they fit nicely with the external G-quartets of quadruplexes. Stimulated by the pioneering studies on the cationic porphyrin TMPyP4 and the natural product telomestatin, follow-up studies have developed, rapidly leading to a large diversity of macrocyclic structures with remarkablequadruplex binding properties and biological activities. In this review we summarize the current state of the art in detailing the three main categories of quadruplex-binding macrocycles described so far (telomestatin-like polyheteroarenes, porphyrins and derivatives, polyammonium cyclophanes), and in addressing both synthetic issues and biological aspects.

Macrocyclic scaffolds are particularly attractive for designing selective G-quadruplex ligands es... more Macrocyclic scaffolds are particularly attractive for designing selective G-quadruplex ligands essentially because, on one hand, they show a poor affinity for the "standard" B-DNA conformation and, on the other hand, they fit nicely with the external G-quartets of quadruplexes. Stimulated by the pioneering studies on the cationic porphyrin TMPyP4 and the natural product telomestatin, follow-up studies have developed, rapidly leading to a large diversity of macrocyclic structures with remarkablequadruplex binding properties and biological activities. In this review we summarize the current state of the art in detailing the three main categories of quadruplex-binding macrocycles described so far (telomestatin-like polyheteroarenes, porphyrins and derivatives, polyammonium cyclophanes), and in addressing both synthetic issues and biological aspects.

Current Protocols in Nucleic Acid Chemistry, 2001

ABSTRACT Absorbance versus temperature curves can provide information on the thermal stability of... more ABSTRACT Absorbance versus temperature curves can provide information on the thermal stability of DNA or RNA quadruplexes. Quadruplex denaturation or renaturation can be followed by recording absorbance at 295 nm rather than 260 nm, the wavelength used to monitor duplex denaturation. This unit describes the use of absorbance versus temperature curves to determine melting temperatures (T(m) values) and model-dependent thermodynamic parameters.

A collection of 26 polyammonium cyclophane-type macrocycles with a large structural diversity has... more A collection of 26 polyammonium cyclophane-type macrocycles with a large structural diversity has been screened for Gquadruplex recognition. A two-step selection procedure based on the FRET-melting assay was carried out enabling identification of macrocycles of high affinity (ΔT 1/2 up to 30 • C) and high selectivity for the human telomeric G-quadruplex. The four selected hits possess sophisticated architectures, more particularly the presence of a pendant side-arm as well as the existence of a particular topological arrangement appear to be strong determinants of quadruplex binding. These compounds are thus likely to create multiple contacts with the target that may be at the origin of their high selectivity, thereby suggesting that this class of macrocycles offers unique advantages for targeting G-quadruplex-DNA.

ChemInform, 2007

ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Chemical Science, 2013

ABSTRACT The effects of modification of the phosphodiester backbone or the guanine bases on G-qua... more ABSTRACT The effects of modification of the phosphodiester backbone or the guanine bases on G-quadruplex formation have been widely investigated. Only a few studies have investigated the effects of deoxyribose or ‘sugar’ modifications on G-quadruplex structure. Here, we evaluated the structural, thermodynamic, and kinetic properties of the parallel quadruplexes formed by the sequence d(TGGGGT) in which each guanine base was substituted, one at a time, with acyclic threoninol nucleic acid (aTNA). We found that all sequences were able to form G-quadruplexes; however, the presence of aTNA resulted in the formation of a mixture of quadruplex structures in some cases. Furthermore, the presence of a single substitution at any position resulted in destabilization of the G-quadruplex relative to that formed by the unmodified sequence. The introduction of the aTNA in terminal quartets was the most detrimental to stability. In addition, kinetic experiments showed that, compared to its unmodified counterpart sequence d(TGGGGT), the substitution of a normal guanine nucleotide by aTNA decelerated quadruplex formation except when the aTNA was at the 5′ most guanine of the sequence. In summary, our studies indicate that the deoxyribose sugar affects the properties of G-quadruplex structures.

Journal of Nucleic Acids, 2010

G-quadruplexes are a family of four-stranded structures stabilized by guanine quartets, in which ... more G-quadruplexes are a family of four-stranded structures stabilized by guanine quartets, in which four planar guanines establish a cyclic array of hydrogen bonds. They are of special interest due to the increasing evidence for their formation in vivo and their possible implication in biology, especially at telomeres and as contributors to gene regulation. Moreover, G-quadruplexes are also formed as a result of self-assembling processes of guanosine derivatives, yielding several interesting motifs such as G-ribbons and G-wires which have peculiar electrical conductivity properties that are being explored as molecular wires.

Journal of Nucleic Acids, 2010

G-quadruplexes are a family of four-stranded structures stabilized by guanine quartets, in which ... more G-quadruplexes are a family of four-stranded structures stabilized by guanine quartets, in which four planar guanines establish a cyclic array of hydrogen bonds. They are of special interest due to the increasing evidence for their formation in vivo and their possible implication in biology, especially at telomeres and as contributors to gene regulation. Moreover, G-quadruplexes are also formed as a result of self-assembling processes of guanosine derivatives, yielding several interesting motifs such as G-ribbons and G-wires which have peculiar electrical conductivity properties that are being explored as molecular wires.

Topics in Current Chemistry, 2012

Guanine quadruplexes (G4) are unusual four-stranded nucleic acid structures formed by G-rich DNA/... more Guanine quadruplexes (G4) are unusual four-stranded nucleic acid structures formed by G-rich DNA/RNA. Beyond their likely biological relevance, the self-assembly, stability, and rigidity of these structures are also interesting for nanotechnology and biotechnology applications. Therefore, efforts are carried out to understand the rules that govern stability and folding of G-quadruplexes. We focus this chapter on tetramolecular conformations which are simple tractable models. We report here the experimental parameters, molecules, and modifications that affect thermal stability and/or association kinetics of these structures. Some chemical modifications which facilitate tetramolecular quadruplex formation and can be useful for nano-or biotechnology are also described.

Proceedings of the National Academy of Sciences, 2003

There is currently great interest in the design of nanodevices that are capable of performing lin... more There is currently great interest in the design of nanodevices that are capable of performing linear or rotary movements. Protein molecular machines are abundant in biology but it has recently been proposed that nucleic acids could also act as nanomolecular machines in model systems. Several types of movements have been described with DNA machines: rotation and "scissors-like" opening and closing. Here we show a nanomachine that is capable of an extension-contraction movement. The simple and robust device described here is composed of a single 21-base oligonucleotide and relies on a duplex-quadruplex equilibrium that may be fueled by the sequential addition of DNA single strands, generating a DNA duplex as a by-product. The interconversion between two well defined topological states induces a 5-nm two-stroke, linear motor-type movement, which is detected by fluorescence resonance energy transfer spectroscopy.

Proceedings of the National Academy of Sciences, 2001

Abbreviations: FRET, fluorescence resonance energy transfer; G4-DNA, quadruplex DNA based on guan... more Abbreviations: FRET, fluorescence resonance energy transfer; G4-DNA, quadruplex DNA based on guanine quartets; TRAP, telomerase repeat amplification protocol. † To whom reprint requests should be addressed.