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Topic Name: Researchers found chirality of G-quadruplexes could grow to several hundred nanometers

Category: Chemical

Research persons: Mihail Barboiu Mihail Barboiu

Location: European Institute of Membranes UMR CNRS 5635, France

Details

Researchers at the European Institute of Membranes (UMR CNRS 5635, Montpellier), led by Mihail Barboiu, found that the chirality of G-quadruplexes, tubular superstructure of a few nanometers, rich in guanine, could grow to several hundred nanometers.

To achieve this performance, they have developed a technique based on the sol-gel process, paving the way to the synthesis of new materials with unique properties of membrane transport of ions for example, comparable to those of natural systems as 'DNA or RNA.

* The molecular chirality is often linked to the presence of asymmetric centers within molecules.The assembly of such molecules in general leads to supramolecular aggregates asymmetrical shape.Yet in the living world non-chirales molecules can form chiral blends, according mechanisms still largely unknown.This type of supramolecular assemblies chiral, the nanometer, is the result of an unbalanced spatial arrangement of molecules interacting.The formation of these supramolecular architectures chiral solution is dynamic and examples of such chiralitérestent rare.

The superstructure G-quadruplexe s rich in guanine ** formed by stacks of stranded helical represent a concrete example of chiral supramolecular architecture. Used in cancer therapy, they have an important role as inhibitors of telomerase, an enzyme involved in cellular aging plays a key role in cell cancerization.The G-quadruplexes naturally consist of nucleic acids, are all the more astonishing that they spontaneously form tubular structures for the transport of ions (ion channel).This example of functional architecture chiral synthesis, frequently encountered in biological systems (DNA, RNA, etc.) is seen by many scientists for some forty years (1).

As part of their studies on materials membrane dynamics (2), Mihail Barboiu *** and his colleagues from the European Institute of Membranes (UMR CNRS 5635, Montpellier) have discovered that the chirality of supramolecular G-quadruplexes could grow on several hundreds of nanometers (3). To accomplish this work, the research team composed of chemists and biochemists, has developed a technique based on the sol-gel process ****.The G-quadruplexes, whose geometry is helical, communicate with their chirality G-quadruplexes neighbors, organized in a hexagonal network.These buildings supramolecular dynamic scaffolding used to form hexagonal rods twisted hybrid organic and inorganic (siloxanes *****), 800 nm in diameter.The slow heat treatment at 400 ° C led to the removal of organic molecules, G-quadruplexes, and the formation of silica propellers.These propellers are several micrometers long and topology is very similar to their fellow supramolecular, G-quadruplexes.The dynamic supramolecular organization has forwarded its chirality in buildings inorganic far superior size (a few micrometers).Researchers from Montpellier issued a first picture of these new chiral materials.

The marriage between self and supramolecular polymerization mineral led to the transmission of supramolecular chirality in a hybrid material. The researchers were surprised to observe that we find the same principle helical growth in the giant sequoias, thereby ensuring their stability.Indeed, the control of the organization to scale supramolecular and his rejoinder hybrid twist on a larger scale, looks astonishingly architecture which ensures the stability of redwoods. This work opens two new prospects. On the one hand, they make it easier to understand from a simple system, as G-quadruplexe, what are the mechanisms of transmission of the chirality in materials far exceeds in size.On the other hand, they open the way to the synthesis of new materials with unique properties of membrane transport, which may be of interest to biologists.Indeed, researchers have recently shown that the membrane materials so prepared could lead ions as effectively as natural systems based nucleic acid (DNA, RNA ...), opening the door to biological and biotechnological applications (4 ).

* Chirality: an object is chiral if it is not superimposed on the image in the mirror. This is the case of the hand, for example. This is the case of the hand, for example.
** Guanine: substance extracted from the guano ** Guanine: substance extracted from the guano
*** Mihail Barboiu is EURYI Award winner in 2004 (European Research Young Investigators)

**** Sol-gel process: It allows you to make a polymer by inorganic chemical reactions simple and at temperatures close to room temperature (20 to 150 ° C)

***** Siloxanes: Class of silicon compounds. The word is derived from siloxane icium sil, ygène ox and ass alk.

Note for G-quadruplex

Nucleic acid sequences which are rich in guanine are capable of forming four-stranded structures called G-quadruplexes (Also known as G-tetrads or G4-DNA). These consist of a square arrangement of guanines (a tetrad), stabilized by Hoogsteen hydrogen bonding. They are further stabilized by the existence of a monovalent cation (especially potassium) in the center of the tetrads. They can be formed of DNA, RNA, LNA and PNA, and may be intramolecular, bimolecular or tetramolecular. Depending on the direction of the strands or parts of a strand that form the tetrads, structures may be described as parallel or antiparallel.

Telomeric quadruplexes
Telomeric repeats in a variety of organisms have been shown to form these structures in vitro, and they have also been shown to form in vivo in some cases. The human telomeric repeat (which is the same for all vertebrates) consists of many repeats of the sequence d(GGTTAG), and the quadruplexes formed by this structure have been well studied by NMR and X-ray crystal structure determination. The formation of these quadruplexes in telomeres has been shown to decrease the activity of the enzyme telomerase, which is responsible for elongating telomeres and is involved in around 85% of all cancers. This is an active target of drug discovery.

Non-telomeric quadruplexes
Recently, there has been increasing interest in quadruplexes in locations other than at the telomere. This was given a large boost by the work by Hurley on the proto-oncogene c-myc[1], which was shown to form a quadruplex in a nuclease hypersensitive region critical for gene activity. Since then, many other genes have been shown to have G-quadruplexes in their promoter regions, including the chicken β-globin gene, human ubiquitin-ligase RFP2 and the proto-oncogenes c-kit, bcl-2, VEGF, H-ras and N-ras. This list is ever-increasing.

Genome-wide surveys based on a quadruplex folding rule have been performed, which have identified 376,000 Putative Quadruplex Sequences (PQS) in the human genome, although not all of these probably form in vivo.  A similar study has identified putative G-quadruplexes in prokaryotes[3].There are several possible models for how quadruplexes could control gene activity, either by upregulation or downregulation. One model is shown below, with G-quadruplex formation in or near a promoter blocking transcription of the gene, and hence de-activating it. In another model, quadruplex formed at the non-coding DNA strand helps to maintain an open conformation of the coding DNA strand and enhance an expression of the respective gene.

Note for Supramolecular electronics

Supramolecular electronics is the experimental field of supramolecular chemistry that bridges the gap between molecular electronics and bulk plastics in the construction of electronic circuitry at the nanoscale 1. In supramolecular electronics, assemblies of pi-conjugated systems on the 5 to 100 nanometer length scale are prepared by molecular self-assembly with the aim to fit these structures between electrodes. With single-molecules as researched in molecular electronics at the 5 nanometer scale this would be impractical. Nanofibers can be prepared from polymers such as polyaniline and polyacetylene 12. Chiral oligo(p-phenylenevinylene)s self-assemble in a controlled fashion into (helical) wires 3. An example of actively researched compounds in this field are certain coronenes.

References
(1) (a) J.T. (1) (a) J.T. Davis, G.P. Davis, G.P. Spada, Chem Soc. Rev. 2007, 36, 296-313; (B) J. Spada, Chem Soc. Rev. 2007, 36, 296-313; (B) J. T. Davis, Angew. Davis, Angew. Chem. Chem. Int. Int. Ed 2004, 43, 668-698. Ed 2004, 43, 668-698.
(2) This work was carried out under the project "Dynamic adaptive materials for separation and sensing Microsystems' - EURYI Program (European Young Investigator) Awards-co-ordinated by European Heads of Research Councils, whose CNRS is a member and European Science Foundation , and supported by the organization participating in the EURYI and Network Programs FP6. See http://64.233.179.104/translate_c?hl=en&u=http://www.esf.org / euryi & prev = / search 3Fq%%% 26hl 3Dcnrs 3Den%%% 26rlz 3D1T4GGIH_enIN242IN242http: / / www.cnrs.fr / chemistry / communication / direct_labos.htm.

3) C. Arnal-Hérault, A. Arnal-Hérault, A. Banu, Mr. Banu, Mr. Barboiu, Mr. Barboiu, Mr. Michau, A. Michau, A. Van der Lee, Amplification and transcription of the dynamic supramolecular chirality of the G-quadruplex, Angew. Van der Lee, Amplification and transcription of the dynamic supramolecular chirality of the G-quadruplex, Angew. Chem. 2007, 119, 4346-4350; Angew. Chem. 2007, 119, 4346-4350; Angew. Chem. Chem. Int. Int. Ed, 2007, 46, 4268-4272-Cover Picture Communications, June 2007. Ed, 2007, 46, 4268-4272-Cover Picture Communications, June 2007.

(4) C. Arnal-Herault, A. Arnal-Herault, A. Pasc-Banu, Mr. Pasc-Banu, Mr. Michau, D. Cot, E. Michau, D. Cot, E. Petit, M. Petit, M. Barboiu, Functional G-Quartet Macroscopic Membrane Films, Angew. Barboiu, Functional G-Quartet Macroscopic Membrane Films, Angew. Chem. Chem. Int. Int. Ed. In 2007, DOI: 10 / 1002/anie.200702605. Ed In 2007, DOI: 10 / 1002/anie.200702605.

Contact
Mihail Barboiu Mihail Barboiu
European Institute of Membranes UMR CNRS 5635

Adaptive Supramolecular Nanosystems Group,
Montpellier
Tel: +33- (0) 4-67149195 Tel: +33- (0) 4-67149195
Email: barboiu@iemm.univ-montp2.fr