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In molecular biology, G-quadruplex secondary structures[1] are formed in nucleic acids by sequences that are rich in guanine. They are helical structures containing guanine tetrads that can form from one,[2] two[3] or four strands.[4] The unimolecular forms often occur naturally near the ends of the chromosomes, better known as the telomeric regions, and in transcriptional regulatory regions of multiple genes and oncogenes.[5] Four guanine bases can associate through Hoogsteen hydrogen bonding to form a square planar structure called a guanine tetrad (also called G-tetrad or G-quartet), and two or more guanine tetrads can stack on top of each other to form a G-quadruplex. The placement and bonding to form G-quadruplexes are not random and serve very unusual functional purposes. The quadruplex structure is further stabilized by the presence of a cation, especially potassium, which sits in a central channel between each pair of tetrads.[2] They can be formed of DNA, RNA, LNA, and PNA, and may be intramolecular, bimolecular, or tetramolecular.[6] Depending on the direction of the strands or parts of a strand that form the tetrads, structures may be described as parallel or antiparallel. G-quadruplex structures can be computationally predicted from DNA or RNA sequence motifs, but their actual structures can be quite varied within and between the motifs, which can number over 100,000 per genome. Their activities in basic genetic processes are an active area of research in telomere, gene regulation, and functional genomics research.[7]

(replacement figure 1)
Structure of a G-quadruplex. Left: a G-tetrad. Right: an intramolecular G-quadruplex
3D Structure of the intramolecular human telomeric G-quadruplex in potassium solution (PDB ID 2HY9). The backbone is represented by a tube. The center of this structure contains three layers of G-tetrads. The hydrogen bonds in these layers are represented by blue dashed lines.

Quadruplex topology[edit]

The length of the nucleic acid sequences involved in tetrad formation determines how the quadruplex folds. Short sequences, consisting of only a single contiguous run of three or more guanine bases, require four individual strands to form a quadruplex. Such a quadruplex is described as tetramolecular, reflecting the requirement of four separate strands. The term G4 DNA was originally reserved for these tetramolecular structures that might play a role in meiosis.[4] However, as currently used in molecular biology, the term G4 can mean G-quadruplexes of any molecularity. Longer sequences, which contain two contiguous runs of three or more guanine bases, where the guanine regions are separated by one or more bases, only require two such sequences to provide enough guanine bases to form a quadruplex. These structures, formed from two separate G-rich strands, are termed bimolecular quadruplexes. Finally, sequences which contain four distinct runs of guanine bases can form stable quadruplex structures by themselves, and a quadruplex formed entirely from a single strand is called an intramolecular quadruplex.[8]

Depending on how the individual runs of guanine bases are arranged in a bimolecular or intramolecular quadruplex, a quadruplex can adopt one of a number of topologies with varying loop configurations.[9] If all strands of DNA proceed in the same direction, the quadruplex is termed parallel. For intramolecular quadruplexes, this means that any loop regions present must be of the propeller type, positioned to the sides of the quadruplex. If one or more of the runs of guanine bases has a 5’-3’ direction opposite to the other runs of guanine bases, the quadruplex is said to have adopted an antiparallel topology. The loops joining runs of guanine bases in intramolecular antiparallel quadruplexes are either diagonal, joining two diagonally opposite runs of guanine bases, or lateral (edgewise) type loops, joining two adjacent runs of guanine base pairs.

In quadruplexes formed from double-stranded DNA, possible interstrand topologies have also been discussed [10] .[11] Interstrand quadruplexes contain guanines that originate from both strands of dsDNA.

Structure and functional role in genome[edit]

Following sequencing of the human genome, many guanine-rich sequences that had the potential to form quadraplexes were discovered.[12] Depending on cell type and cell cycle, mediating factors such as DNA-binding proteins like chromatin, composed of DNA tightly wound around histone proteins, and other environmental conditions and stresses affect the dynamic formation of quadraplexes. For instance, quantitative assessments of the thermodynamics of molecular crowding indicate that the antiparallel g-quadruplex is stabilized by molecular crowding.[13] This effect seems to be mediated by alteration of the hydration of the DNA and its effect on Hoogsteen base pair bonding.[14] These quadruplexes seemed to readily occur at the ends of chromosome. In addition, the propensity of g-quadruplex formation during transcription in RNA sequences with the potential to form mutually exclusive hairpin or G-quadruplex structures depends heavily on the position of the hairpin-forming sequence.[15]

Because repair enzymes would naturally recognize ends of linear chromosomes as damaged DNA and would process them as such to harmful effect for the cell, clear signaling and tight regulation is needed at the ends of linear chromosomes. Telomeres function to provide this signaling. Telomeres, rich in guanine and with a propensity to form g-quadruplexes, are located at the terminal ends of chromosomes and help maintain genome integrity by protecting these vulnerable terminal ends from instability.

These telomeric regions are characterized by long regions of double-stranded CCCTAA:TTAGGG repeats. The repeats end with a 3’ protrusion of between 10 and 50 single-stranded TTAGGG repeats. The heterodimeric complex ribonucleoprotein enzyme telomerase adds TTAGGG repeats at the 3’ end of DNA strands. At these 3’ end protrusions, the G-rich overhang can form secondary structures such as G-quadraplexes if the overhang is longer than four TTAGGG repeats. The presence of these structures prevent telomere elongation by the telomerase complex.[16]

Telomeric quadruplexes[edit]

Telomeric repeats in a variety of organisms have been shown to form these quadruplex structures in vitro, and subsequently they have also been shown to form in vivo.[17][18] The human telomeric repeat (which is the same for all vertebrates) consists of many repeats of the sequenced (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 maintaining length of telomeres and is involved in around 85% of all cancers. This is an active target of drug discovery, including telomestatin.

Non-telomeric quadruplexes[edit]

Quadruplexes are present in locations other than at the telomere. The proto-oncogene c-myc forms a quadruplex in a nuclease hypersensitive region critical for gene activity.[19][20] Other genes shown to form G-quadruplexes in their promoter regions include the chicken β-globin gene, human ubiquitin-ligase RFP2, and the proto-oncogenes c-kit, bcl-2, VEGF, H-ras and N-ras.[21][22][23]

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.[24] A similar study has identified putative G-quadruplexes in prokaryotes.[25] There are several possible models for how quadruplexes could influence 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.

Model for quadruplex-mediated down-regulation of gene expression[26]

G-Quadruplex function[edit]

It has been suggested that quadruplex formation plays a role in immunoglobulin heavy chain switching.[27] As cells have evolved mechanisms for resolving (i.e., unwinding) quadruplexes that form, quadruplex formation may be potentially damaging for a cell; the helicases WRN and Bloom syndrome protein have a high affinity for resolving DNA G-quadruplexes.[28] The DEAH/RHA helicase, DHX36, has also been identified as a key G-quadruplex resolvase.[29][30] More recently, there are many studies that implicate quadruplexes in both positive and negative transcriptional regulation, and in allowing programmed recombination of immunologlobin heavy genes and the pilin antigenic variation system of the pathogenic Neisseria.[31] The roles of quadruplex structure in translation control are not as well explored. The direct visualization of G-quadruplex structures in human cells[32] as well as the co-crystal structure of an RNA helicase bound to a G-quadruplex[33] have provided important confirmations of their relevance to cell biology. The potential positive and negative roles of quadruplexes in telomere replication and function remains controversial. T-loops and G-quadruplexes are described as the two tertiary DNA structures that protect telomere ends and regulate telomere length.[34]

Ligands which bind quadruplexes[edit]

One way of inducing or stabilizing G-quadruplex formation is to introduce a molecule which can bind to the G-quadruplex structure. A number of ligands, both small molecules and proteins, which can bind to the G-quadruplex. These ligands can be naturally occurring or synthetic. This has become an increasingly large field of research in genetics, biochemistry, and pharmacology.

A number of naturally occurring proteins have been identified which selectively bind to G-quadruplexes. These include the helicases implicated in Bloom's and Werner's syndromes and the Saccharomyces cerevisiae protein RAP1. In human organism, about 80 DNA or RNA quadruplex binding proteins were identified. [35] Recently, was found that all characterized G-quadruplex binding proteins share a 20 amino acid long motif/domain (RGRGR GRGGG SGGSG GRGRG) called NIQI (Novel Interesting Quadruplex Interaction Motif) [36]which is similar to the previously described RG-rich domain (RRGDG RRRGG GGRGQ GGRGR GGGFKG) of the FMR1 G-quadruplex binding protein [37] . An artificially derived three zinc finger protein called Gq1, which is specific for G-quadruplexes has also been developed, as have specific antibodies.

Cationic porphyrins have been shown to bind intercalatively with G-quadruplexes, as well as the molecule telomestatin.

Quadruplex prediction techniques[edit]

Identifying and predicting sequences which have the capacity to form quadruplexes is an important tool in further understanding their role. Generally, a simple pattern match is used for searching for possible intrastrand quadruplex forming sequences: d(G3+N1-7G3+N1-7G3+N1-7G3+), where N is any nucleotide base (including guanine).[38] This rule has been widely used in on-line algorithms. Although the rule effectively identifies sites of G-quadruplex formation it also identifies a subset of the imperfect homopurine mirror repeats capable of triplex formation[39] and C-strand i-motif formation.[40] Moreover, these sequences also have the capacity to form slipped and foldback structures that are implicit intermediates in the formation of both quadruplex[41] and triplex DNA[42] structures. In one study[43] it was found that the observed number per base pair (i.e. the frequency) of these motifs has increased rapidly in the eumetazoa for which complete genomic sequences are available. This suggests that the sequences may be under positive selection enabled by the evolution of systems capable of suppressing non-B structure formation.

Role in neurological disorders[edit]

G-quadruplexes have been implicated in neurological disorders through two main mechanisms. The first is through expansions of G-repeats within genes that lead to the formation of G-quadruplex structures that directly cause disease, as is the case with the C9orf72 gene and amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD). The second mechanism is through mutations that affect the expression of G-quadruplex binding proteins, as seen in the FMR1 gene and Fragile X Syndrome.[44]

The C9orf72 gene codes for the protein C9orf72 which is found throughout the brain in neuronal cytoplasm and at presynaptic terminals.[45] Mutations of the C9orf72 gene have been linked to the development of FTD and ALS.[46] These two diseases have a causal relationship to GGGGCC (G4C2) repeats within the 1st intron of C9orf72 gene. Normal individuals typically have around 2 to 8 G4C2 repeats, but individuals with FTD or ALS have from 500 to several thousand G4C2 repeats.[47][48] The transcribed RNA of these repeats have been shown to form stable G-quadruplexes, with evidence showing that the G4C2 repeats in DNA have the ability to form mixed parallel-antiparallel G-quadruplex structures as well.[49][50] These RNA transcripts containing G4C2 repeats were shown to bind and separate a wide variety of proteins, including nucleolin. Nucleolin is involved in the synthesis and maturation of ribosomes within the nucleus, and separation of nucleolin by the mutated RNA transcripts impairs nucleolar function and ribosomal RNA synthesis.[51]

Fragile X mental retardation protein (FMRP) is a widely expressed protein coded by the fragile X mental retardation gene 1 (FMR1) that binds to G-quadruplex secondary structures in neurons and is involved in synaptic plasticity.[52] FMRP acts as a negative regulator of translation, and its binding stabilizes G-quadruplex structures in mRNA transcripts, inhibiting ribosome elongation of mRNA in the neuron's dendrite and controlling the timing of the transcript's expression.[53][54] Mutations of this gene can cause the development of Fragile X Syndrome, autism, and other neurological disorders.[55] Specifically, Fragile X Syndrome is caused by an increase from 50 to over 200 CGG repeats within exon 13 of the FMR1 gene. This repeat expansion promotes DNA methylation and other epigenetic heterochromatin modifications of FMR1 that prevent the transcription of the gene, leading to pathological low levels of FMRP.[56][57]

Therapeutic approaches[edit]

Antisense-mediated interventions and small-molecule ligands are common strategies used to target neurological diseases linked to G-quadruplex expansion repeats. Therefore, these techniques are especially advantageous for targeting neurological diseases that have a gain-of-function mechanism, which is when the altered gene product has a new function or new expression of a gene; this has been detected in the C9orf72 (chromosome 9 open reading frame 72).[58]

Antisense therapy is the process by which synthesized strands of nucleic acids are used to bind directly and specifically to the mRNA produced by a certain gene, which will inactivate it. Antisense oligonucleotides (ASOs) are commonly used to target C9orf72 RNA of the G-quadruplex GGGGCC expansion repeat region, which has lowered the toxicity in cellular models of C9orf72.[59][60][61] ASOs have previously been used to restore normal phenotypes in other neurological diseases that have gain-of-function mechanisms, the only difference is that it was used in the absence of G-quadruplex expansion repeat regions.[62][63][64][65]

Another commonly used technique is the utilization of small-molecule ligands. These can be used to target G-quadruplex regions that cause neurological disorders. Approximately 1,000 various G-quadruplex ligands exist in which they are able to interact via their aromatic rings; this allows the small-molecule ligands to stack on the planar terminal tetrads within the G-quadruplex regions. A disadvantage of using small-molecule ligands as a therapeutic technique is that specificity is difficult to manage due to the variability of G-quadruplexes in their primary sequences, orientation, thermodynamic stability, and nucleic acid strand stoichiometry. As of now, no single small-molecule ligand has been able to be 100% specific for a single G-quadruplex sequence.[66][67] However, a cationic porphyrin known as TMPyP4 is able to bind to the C9orf72 GGGGCC repeat region, which causes the G-quadruplex repeat region to unfold and lose its interactions with proteins causing it to lose its functionality.[68] Small-molecule ligands, composed primarily of lead, can target GGGGCC repeat regions as well and ultimately decreased both repeat-associated non-ATG translation and RNA foci in neuron cells derived from patients with Amyotrophic lateral sclerosis (ALS). This provides evidence that small-molecule ligands are an effective and efficient process to target GGGGCC regions, and that specificity for small-molecule ligand binding is a feasible goal for the scientific community.

Metal complexes have a number of features that make them particularly suitable as G4 DNA binders and therefore as potential drugs. While the metal plays largely a structural role in most G4 binders, there are also examples where it interacts directly with G4s by electrostatic interactions or direct coordination with nucleobases.[69]


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External links[edit]

Quadruplex websites[edit]

Tools to predict G-quadruplex motifs[edit]