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Stability and kinetics of G-quadruplex structures.

Lane AN, Chaires JB, Gray RD, Trent JO - Nucleic Acids Res. (2008)

Bottom Line: Significant gaps in the literature have been identified, that should be filled by a systematic study of well-defined quadruplexes not only to provide the basic understanding of stability both for design purposes, but also as it relates to in vivo occurrence of quadruplexes.Quadruplex structures fold and unfold comparatively slowly, and DNA unwinding events associated with transcription and replication may be operating far from equilibrium.The kinetics of formation and resolution of quadruplexes, and methodologies are discussed in the context of stability and their possible biological occurrence.

View Article: PubMed Central - PubMed

Affiliation: Structural Biology Program, JG Brown Cancer Center, University of Louisville, KY 40202, USA. anlane01@gwise.louisville.edu

ABSTRACT
In this review, we give an overview of recent literature on the structure and stability of unimolecular G-rich quadruplex structures that are relevant to drug design and for in vivo function. The unifying theme in this review is energetics. The thermodynamic stability of quadruplexes has not been studied in the same detail as DNA and RNA duplexes, and there are important differences in the balance of forces between these classes of folded oligonucleotides. We provide an overview of the principles of stability and where available the experimental data that report on these principles. Significant gaps in the literature have been identified, that should be filled by a systematic study of well-defined quadruplexes not only to provide the basic understanding of stability both for design purposes, but also as it relates to in vivo occurrence of quadruplexes. Techniques that are commonly applied to the determination of the structure, stability and folding are discussed in terms of information content and limitations. Quadruplex structures fold and unfold comparatively slowly, and DNA unwinding events associated with transcription and replication may be operating far from equilibrium. The kinetics of formation and resolution of quadruplexes, and methodologies are discussed in the context of stability and their possible biological occurrence.

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Formal model for formation of an internal G-quadruplex or other intramolecular structure. Duplex DNA with a G-quadruplex potential sequence (top) unwinds and histones redistribute, leading to base-pair dissociation and formation of an open loop (middle). The G-rich strand forms a unimolecular G-quadruplex structure in the presence of a single-stranded complementary C-rich strand. This potentially could form an intramolecular i-motif as shown (third from top). The quadruplex and/or the C-rich strand may be stabilized by proteins (as shown at bottom) or other ligands. The binding energy required to overcome the unwinding is discussed in the text.
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Figure 9: Formal model for formation of an internal G-quadruplex or other intramolecular structure. Duplex DNA with a G-quadruplex potential sequence (top) unwinds and histones redistribute, leading to base-pair dissociation and formation of an open loop (middle). The G-rich strand forms a unimolecular G-quadruplex structure in the presence of a single-stranded complementary C-rich strand. This potentially could form an intramolecular i-motif as shown (third from top). The quadruplex and/or the C-rich strand may be stabilized by proteins (as shown at bottom) or other ligands. The binding energy required to overcome the unwinding is discussed in the text.

Mentions: The folding of a single-strand G-rich overhang such as the one that exists in telomeres is a very different proposition from the formation of a G-quadruplex in an internal position, such as identified in numerous promoters (60,235). This area of research has been recently reviewed (236). In the former case, the folding is free to occur from an unconstrained end, and does so on a potentially stabilizing nucleus of double-stranded B-like DNA (59). In contrast, from the point of view of energetics, the internal G-quadruplexes require the separation of the DNA strands to form a loop (very unfavorable) followed by the G-rich strand forming a quartet while being tethered at both ends, leaving the complementary strand as a loop, or as an i-motif as shown in Figure 9. Based on estimates of the energies of formation of these structures (134,237,238), it is possible to calculate the cost of formation of such a structure, as follows.Figure 9.


Stability and kinetics of G-quadruplex structures.

Lane AN, Chaires JB, Gray RD, Trent JO - Nucleic Acids Res. (2008)

Formal model for formation of an internal G-quadruplex or other intramolecular structure. Duplex DNA with a G-quadruplex potential sequence (top) unwinds and histones redistribute, leading to base-pair dissociation and formation of an open loop (middle). The G-rich strand forms a unimolecular G-quadruplex structure in the presence of a single-stranded complementary C-rich strand. This potentially could form an intramolecular i-motif as shown (third from top). The quadruplex and/or the C-rich strand may be stabilized by proteins (as shown at bottom) or other ligands. The binding energy required to overcome the unwinding is discussed in the text.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2553573&req=5

Figure 9: Formal model for formation of an internal G-quadruplex or other intramolecular structure. Duplex DNA with a G-quadruplex potential sequence (top) unwinds and histones redistribute, leading to base-pair dissociation and formation of an open loop (middle). The G-rich strand forms a unimolecular G-quadruplex structure in the presence of a single-stranded complementary C-rich strand. This potentially could form an intramolecular i-motif as shown (third from top). The quadruplex and/or the C-rich strand may be stabilized by proteins (as shown at bottom) or other ligands. The binding energy required to overcome the unwinding is discussed in the text.
Mentions: The folding of a single-strand G-rich overhang such as the one that exists in telomeres is a very different proposition from the formation of a G-quadruplex in an internal position, such as identified in numerous promoters (60,235). This area of research has been recently reviewed (236). In the former case, the folding is free to occur from an unconstrained end, and does so on a potentially stabilizing nucleus of double-stranded B-like DNA (59). In contrast, from the point of view of energetics, the internal G-quadruplexes require the separation of the DNA strands to form a loop (very unfavorable) followed by the G-rich strand forming a quartet while being tethered at both ends, leaving the complementary strand as a loop, or as an i-motif as shown in Figure 9. Based on estimates of the energies of formation of these structures (134,237,238), it is possible to calculate the cost of formation of such a structure, as follows.Figure 9.

Bottom Line: Significant gaps in the literature have been identified, that should be filled by a systematic study of well-defined quadruplexes not only to provide the basic understanding of stability both for design purposes, but also as it relates to in vivo occurrence of quadruplexes.Quadruplex structures fold and unfold comparatively slowly, and DNA unwinding events associated with transcription and replication may be operating far from equilibrium.The kinetics of formation and resolution of quadruplexes, and methodologies are discussed in the context of stability and their possible biological occurrence.

View Article: PubMed Central - PubMed

Affiliation: Structural Biology Program, JG Brown Cancer Center, University of Louisville, KY 40202, USA. anlane01@gwise.louisville.edu

ABSTRACT
In this review, we give an overview of recent literature on the structure and stability of unimolecular G-rich quadruplex structures that are relevant to drug design and for in vivo function. The unifying theme in this review is energetics. The thermodynamic stability of quadruplexes has not been studied in the same detail as DNA and RNA duplexes, and there are important differences in the balance of forces between these classes of folded oligonucleotides. We provide an overview of the principles of stability and where available the experimental data that report on these principles. Significant gaps in the literature have been identified, that should be filled by a systematic study of well-defined quadruplexes not only to provide the basic understanding of stability both for design purposes, but also as it relates to in vivo occurrence of quadruplexes. Techniques that are commonly applied to the determination of the structure, stability and folding are discussed in terms of information content and limitations. Quadruplex structures fold and unfold comparatively slowly, and DNA unwinding events associated with transcription and replication may be operating far from equilibrium. The kinetics of formation and resolution of quadruplexes, and methodologies are discussed in the context of stability and their possible biological occurrence.

Show MeSH
Related in: MedlinePlus