Quadruplex Nucleic Acids: Volume 7 (RSC Biomolecular Sciences) - Hardcover

Hardcover

ISBN 10: 0854043748 ISBN 13: 9780854043743

Verlag: Royal Society of Chemistry, 2006

Inhaltsangabe

Guanine rich DNA has been known for decades to form unusual structures, although their biological relevance was little understood. Recent advances have demonstrated that quadruplex structures can play a role in gene expression and provide opportunities for a new class of anticancer therapeutics. A number of quadruplex-specific proteins have also been discovered. Quadruplex Nucleic Acids discusses all aspects of the fundamentals of quadruplex structures, including their structure in solution and the crystalline state, the kinetics of quadruplex folding, and the role of cations in structure and stability. The biology of quadruplexes and G-rich genomic regions and G-quartets in supramolecular chemistry and nanoscience are also considered. Surveying the current state of knowledge, and with contributions from leading experts, this is the first comprehensive review of this rapidly growing area. Quadruplex Nucleic Acids is ideal for researchers interested in areas related to chemistry, chemical biology, medicinal chemistry, molecular pharmacology, and structural and molecular biology.

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Guanine rich DNA has been known for decades to form unusual structures, although their biological relevance was little understood. Recent advances have demonstrated that quadruplex structures can play a role in gene expression and provide opportunities for a new class of anticancer therapeutics. A number of quadruplex-specific proteins have also been discovered. Quadruplex Nucleic Acids discusses all aspects of the fundamentals of quadruplex structures, including their structure in solution and the crystalline state, the kinetics of quadruplex folding, and the role of cations in structure and stability. The biology of quadruplexes and G-rich genomic regions and G-quartets in supramolecular chemistry and nanoscience are also considered. Surveying the current state of knowledge, and with contributions from leading experts, this is the first comprehensive review of this rapidly growing area. Quadruplex Nucleic Acids is ideal for researchers interested in areas related to chemistry, chemical biology, medicinal chemistry, molecular pharmacology, and structural and molecular biology.

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Quadruplex Nucleic Acids

By Stephen Neidle, Shankar Balasubramanian

The Royal Society of Chemistry

Copyright © 2006 The Royal Society of Chemistry
All rights reserved.

ISBN: 978-0-85404-374-3

Contents

Chapter 1 Fundamentals of Quadruplex Structures Gary Nigel Parkinson, 1, 
Chapter 2 Energetics, Kinetics and Dynamics of Quadruplex Folding Jean-Louis Mergny, Julien Gros, Anne De Cian, Anne Bourdoncle, Frédéric Rosu, Barbara Saccà, Lionel Guittat, Samir Amrane, Martin Mills, Patrizia Alberti, Masashi Takasugi and Laurent Lacroix, 31, 
Chapter 3 Structural Diversity of G-Quadruplex Scaffolds Anh Tuân Phan, Vitaly Kuryavyi, Kim Ngoc Luu and Dinshaw J. Patel, 81, 
Chapter 4 The Role of Cations in Determining Quadruplex Structure and Stability Nicholas V. Hud and Janez Plavec, 100, 
Chapter 5 DNA Quadruplex–Ligand Recognition: Structure and Dynamics Mark S. Searle and Graham D. Balkwill, 131, 
Chapter 6 Quadruplex Ligand Recognition: Biological Aspects Jean-François Riou, Dennis Gomez, Hamid Morjani and Chantal Trentesaux, 154, 
Chapter 7 DNA Quadruplexes and Gene Regulation Thomas S. Dexheimer, Michael Fry and Laurence H. Hurley, 180, 
Chapter 8 Quadruplexes in the Genome Julian Huppert, 208, 
Chapter 9 Quadruplexes and the Biology of G-Rich Genomic Regions Nancy Maizels, 228, 
Chapter 10 The G-Quartet in Supramolecular Chemistry and Nanoscience Mark S. Kaucher, William A. Harrell JR. and Jeffery T. Davis, 253, 
Subject Index, 297, 

CHAPTER 1

Fundamentals of Quadruplex Structures

GARY NIGEL PARKINSON

The School of Pharmacy, University of London, 29–39 Brunswick Square, Bloomsbury, WC1N 1AX, London, UK

1.1 Background and Introduction to Quadruplexes

Self-association of guanosine at millimolar concentrations has been observed in solution since the 19th century as characterized by the ready formation of polycrystalline gels. In the 1960s Gellert et al. determined the associated guanine bases to be in a tetrameric arrangement by crystallographic methods, described simply as a G-quartet arrangement. The four guanine bases form a square co-planar array where each base is both a hydrogen bond donor and hydrogen bond acceptor. Utilization of both the N1 and N2 of one face with the O6 and N7 of the second face on guanosine yields eight hydrogen bonds per planar G-quartet [Figure 1(a-b)]. With the development of chemical synthesis of extended polyguanine oligonucleotides strands additional associations were observed in the laboratory environment. CD and IR spectroscopy confirmed the same self-assembly and association of the guanines into G-quartets, while X-ray fiber diffraction studies demonstrated a four-stranded motif with stacked tetrad planes, termed quadruplexes. These stacked tetrads align themselves to give a similar appearance to that of duplex DNA [Figure 2(a)], characterized by a regular rise and twist between the tetrad planes and generating a right-handed helical twist [Figure 2(c)]. In this case the phosphate backbones, linking the nucleosides together, generate four grooves of variable width, instead of two, giving the quadruplex DNA motif a characteristic duplex DNA feel.

Interest in the structural arrangements of G-quadruplexes was ignited in the early 1990s by the identification of G-rich repetitive sequences located at the end of chromosomes and a protein, with a reverse transcriptase activity, involved in their maintenance. This ground-breaking work was carried out by Blackburn et al. in Joe Gall's research group. They applied sequencing techniques developed previously in Sanger's research laboratory in the late 1970s, a group that was conducting the first comprehensive sequencing experiments on genomic material. It was quickly realized that these guanine-rich repetitive telomeric DNA sequences could form higher order structures and were likely to be involved in chromosomal maintenance. Structural studies on the telomeric sequences revealed both parallel and anti-parallel strand orientations, as well as mixed anti and syn glycosidic torsion angles with the specific features of the quadruplex structural motif dependent upon sequence. The structures determined for the telomeric 3' overhang were of particular interest in terms of chromosomal DNA packaging, and molecular self-assembly, particularly as these G-rich sequences can form compact, well-defined and stable structural motifs.

1.2 Fundamental Components of DNA and RNA

The following is a very basic overview of nucleic acids and their associated properties, focused in areas that relate to quadruplex structure. For a more comprehensive description references 15–19 provide excellent reading. Nucleic acids are polymers of nucleotide units. Each nucleotide unit is composed of three important building blocks: the bases, sugars, and phosphate groups. The nucleoside consists of a base attached to a pentose sugar ring [Figure 3(a)]. In RNA the sugar is a ribose, and in DNA a deoxyribose. The unmodified bases utilized in DNA comprise guanine, cytosine, adenine, and thymine, while for RNA the thymine base is substituted by uracil. The phosphate groups are attached at the 5' side of the nucleoside serving as the linking element between the nucleosides to form a nucleotide. Polymers formed from these three basic components have particular properties that make them ideal for the long-term storage of genetic information in living cells. The nucleotide units are chemically stable and the individual strands have the ability to associate together via complementary bases to form a stacked duplex structure. These polymers are then able to store complimentary copies of genetic information in a compact form that can both disassociate and re-associate.

1.2.1 Building Blocks

The bases are the key components that confer chemical variability to DNA/ RNA. The bases have complementary hydrogen bond donors and acceptors that generate specific associations between bases. There are two faces involved in hydrogen bond formation, the Watson–Crick and the Hoogsteen face, as shown in Figure 3(b). Association via base pairing is normally seen between purines (Guanine, Adenine) and pyrimidines, (Thymine, Cytosine, and Uracil) bases utilizing the basic Watson–Crick base-pairing motif. The G:C base pairing, with its three hydrogen bonds is more stable than the A:T/A:U base pairing with only two hydrogen bonds. This is partially reflected in the higher melting temperatures for GC rich sequences. Other hydrogen bonding arrangements are possible between base pairs and these include a reversed Watson–Crick, a GT wobble pair as well as the use of the Hoogsteen face to give Hoogsteen pairings and reversed Hoogsteen pairings. It is the additional use of the Hoogsteen faces that is critical in the formation and stabilization of tetrads [Figure 3(b)]. The bases with their nitrogen atoms have the added capability to change protonation states based on pH. At neutral pH standard base pairing occurs but at elevated (pH >9.2) or reduced pH (pH <4.2) additional base associations have been observed. The bases are covalently linked to the sugar via the glycosylic bond. The energy minima conformations available to this linkage, within an extended nucleic acid structure, are important in determining how DNA folds and the stability of these folded structures. This dihedral angle linkage χ defined as O4'-C1'-N9-C4 for purines and O4'-C1'-N1-C2 for pyrimidine bases, Figure 3(c). Glycosidic torsion angles in duplex DNA/ RNA fall into two tightly confined conformations. The related orientations adopted by the stacked bases have significant consequences for the overall shape and depth of the DNA/RNA grooves, altering the width, shape, and hydrogen bonding pattern. Two of the most common conformations observed in folded DNA structures are syn and anti shown in Figure 3(c), where syn (0< χ <90°) and anti (– 120< χ <180°).

The pentose sugars also have a critical impact on the conformation of nucleic acid structures. They are non-planar with several energetically stable conformations. In duplex DNA/RNA structures the C2'- endo and C3'-endo conformation are the two most commonly observed [Figure 3(d)]. In an RNA duplex arrangement the sugar conformation is generally restricted to C3'-endo, partly due to steric hindrance, and partly due to hydrogen bonding associated with the O2' hydroxyl group on the pentose sugar. In the case of DNA (deoxyribose) the removal of the hydroxyl group at the O2 position allows additional energetically favorable sugar pucker conformations. The energy barrier between C2'-endo to C3'-endo sugar pucker is 8–21 kJ. In B-form DNA for example, the sugar is primarily in the C2 conformation. The same C2 sugar pucker is commonly observed in G-quadruplex structures for nucleosides involved in tetrad formation. In addition a strong link exists between sugar pucker and the glycosidic torsion angle in extended nucleic acid structures, particularly as C3' and C4' atoms of the sugar also form part of the backbone structure. The sugars have no protonation sites however, the O4' oxygens are extensively utilized by waters forming a network of hydrogen bonding interactions that contribute to the stability of nucleic acid structures.

In nucleic acid structures the phosphate groups are the most exposed and susceptible elements to the effects of solvent. Salt concentrations and levels of hydration have a profound effect on nucleic acid structure, as demonstrated by the salt dependent transition from B to A form DNA. The linking phosphodiester groups have a formal minus one charge resulting in a repulsive electrostatic interaction with other phosphate groups along its own chain and with other associated chains. In addition, the phosphomonoester group at the 5' terminal end of the DNA/RNA strand introduces one extra charge. All these charged oxygen atoms on the phosphate groups are commonly counter balanced by water molecules and metal ions, stabilizing grooves and loop motifs. The consequence of the repulsive negative charges along the phosphate backbone is also apparent within quadruplex structures in modulating folding and the arrangement of loops that link adjacent strands together.

The extended phosphate backbone also introduces a great potential for conformational variability in nucleic acids structures. The DNA backbone consists of six atoms compared to the three in the protein backbone; consequently the backbone conformation is defined by six dihedral angles [Figure 3(b)]. This apparent variability however, is greatly limited by steric constraints. For example several of the backbone torsion angles (α, β, γ, ζ) are restricted to three energetically favorable orientations, albeit with low energy barriers. This results in three broad energy minimas, -60, 60, 180°. It would be still expected that a large number of backbone conformations would be observed in nucleic structures. This indeed is seen for single nucleotide structures, however in extended polynucleotides bound to complementary strands, other factors take over in the efficient compaction of the units into higher order helical structures. Within these duplex arrangements it is observed that certain dihedral angles associate together into sets of low-energy conformations. One such arrangement identified as BI/BII comes from the linked interplay of two dihedrals (ζ and ε). Several other relationships have also been identified, involving for example, α and γ. In addition some dihedral angles are tightly constrained to the sugar pucker conformation such as δ and ε. Other factors affecting backbone conformation come from packing together discrete DNA or RNA structures, either by association in solution or by the tight packing within a crystal lattice. Visually the distribution of backbone dihedral angles is well represented by the use of a wheel plot. An example is show in Figure 4(a) for B-form DNA where the lines represent individual dihedral angles for each nucleotide unit. The clustering and tight distribution of dihedrals can be seen. For comparison, wheel plots are shown for an anti-parallel quadruplex structure, Figure 4(b) and a parallel quadruplexes arrangement Figure 4(c). The similarity in dihedral angle distribution and clustering in these two plots, when compared to duplex B-form DNA, is striking. The obvious difference seen in the anti-parallel quadruplex is the distribution of both syn and anti conformations for the glycosylic torsion angles. Quadruplex structures, in common with RNA structures and unlike helical DNA have single stranded nucleotides unconstrained by normal Watson–Crick base pairing. These single stranded runs have a great deal of flexibility, and are structurally more versatile, typically involved in inter and intra molecular contacts. The conformational flexibility available to the backbone is a key factor in how quadruplexes fold and pack together.

1.2.2 DNA/RNA as a Helical Structure

One view of double stranded DNA was as a featureless linear rod for the storage of genetic information. This view was quickly revised to one of a standard, double stranded B-form DNA, associated with the chromosome bent around chromatin and packaged into the nucleus. Its passive role was revised again as it soon became apparent that structural flexibility was required for DNA to function. In fact, this structural heterogeneity observed in DNA has long been explored and for the case of duplex DNA, classified into several diverse structural groupings A, B, C, D. These motifs and their role in a biological setting has long been sort. A common theme for all these forms of DNA is in a stacked duplex arrangement, with anti-parallel polynucleotide strands (the 5'-3 '-phosphodiester backbone linkages running in opposite directions) forming a right-handed stacked helix. A schematic of B-form DNA, the most common motif found in a biological setting is shown in Figure 2(a),many of its most important characteristics are highlighted. Key structural features for B-form DNA and other forms are laid out in Table 1, tabulated from X-ray structural data. There is great structural diversity available to DNA and one of the more unusual polymorph of duplex DNA is the Z-form. This motif has a left handed helical rise, alternating syn-anti glycosidic angles with variable groove widths. Structural descriptors for the DNA are included in Table 1 for comparison. A structure of a B to Z-form DNA transition has recently been determined by X-ray crystallography. In addition to single and double stranded DNA, the polynucleotide strands can associate into a three-stranded arrangement termed a triplex [Figure 2(b)], by the inclusion of a third strand into the major groove of duplex DNA. This is accomplished by utilizing additional hydrogen bonding and protonation states of the bases. The association of four polynucleotide strands termed a quadruplex only adds to the structural diversity seen in nucleic acid structure. Even though quadruplexes with their four strands might be considered a more diverse polymorph of DNA, they still retain characteristics that are similar to their double stranded cousins. The torsion angles adopt a range of values that are characteristic of duplex DNA, the bases also stack with a helical twist, while the base-pairs utilize standard Watson–Crick and Hoogsteen hydrogen bonding faces. In addition the dihedrals and sugar pucker conformations adopt similar low energy conformations to those observed in other DNA structural motifs. Characteristic structural descriptors of G-quadruplexes are tabulated in Table 1, highlighting their similarity to other forms of DNA, particularly to the B-form.

1.2.3 Stabilizing Factors in Quadruplexes

The same stabilizing factors found in duplex DNA structures such as base stacking, hydrogen bonding, hydration structure, and electrostatic interactions are associated with quadruplex DNA structures, although in G-tetrads only guanine (purine) base stacking needs to be accommodated in G-quadruplex formation. In contrast to these stabilizing factors, an important component of quadruplex instability comes from the arrangement of the guanine O6 carbonyl groups central to the G-quartet. The O6 atoms form a square planar arrangement for each tetrad, with a twist of 30° and rise of 3.3 A between each tetrad step forming a bipyramidal antiprismatic arrangement for the eight O6 atoms. These negatively charged cavities located between the G-tetrads need to be stabilized by the coordination of cations [Figure 5(a–b)]. The selection of a suitable cation, based on size and charge, dramatically determines the overall stability of the final folded quadruplex. For all types of DNA/RNA, where strands associate, grooves are formed from the linked phosphate backbones, creating an extended buried channel of hydrogen bond donors and acceptors. These channels are populated by water molecules, ordered into hydration shells linking together the bases, sugars to the charged phosphate atoms, located on the outer surface, stabilizing the folded DNA structures.

1.2.3.1 Base-Stacking

The bases in DNA are non-polar in nature and have unfavorable interactions with polar solvents. Paired bases will then associate and stack on each other in order to reduce the area exposed to the solvent. Stability is then provided to the DNA helices by the stacking of the bases through a combination of hydrophobic, electrostatic, and van der Waals forces. In addition a small negative charge is also associated with the stacked bases providing a slight tendency for the bases to repel each other. The stacked bases are polarized resulting in the planar face of an aromatic molecule becoming electron rich, while the hydrogens around the edge of the ring become electron poor. In canonical B-DNA stacking energies have been estimated to be between -9.5 and -13.2 kcal mol-1 for GC base-pair steps, whereas an AT base-pair steps have a lower stacking energy of about -5.4 kcal mol-1. These stacked bases cannot sit directly on each other due to steric constraints but are twisted about the helical axis. The distance between the bases pairs is defined as the rise while the rotation about the helical axis is defined as the twist [Figure 6(a)]. Table 1 has a list of typical values of rise and twist for the different DNA forms. Other parameters such as roll, slide, and tilt are used to provide a detailed description of the bases relative to one another and to the global helical axis. Variations in roll and tilt are critical in changing DNA structural motifs say from B to A forms, and to give DNA a global buckle and bend required in the packaging of DNA around the histone, or other protein scaffolds.

(Continues...)

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Details zur Ausgabe

• Verlag: Royal Society of Chemistry
• Erscheinungsdatum: 2006
• Sprache: Englisch
• ISBN 10: 0854043748
• ISBN 13: 9780854043743
• Einband: Tapa dura
• Anzahl der Seiten: 301
• Herausgeber: Neidle Stephen, Balasubramanian Shankar
• Kontakt zum Hersteller: Nicht verfügbar
• Verantwortliche Person: Nicht verfügbar