In molecular biology,
G-quadruplex secondary structures are formed
in nucleic acids by sequences that are rich in guanine. They are
helical structures containing guanine tetrads that can form from
one, two or four strands. 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. Four guanine bases can associate
through Hoogsteen hydrogen bonding to form a square planar structure
called a guanine tetrad, 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. 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.
G-quadruplex structures can be
computationally predicted from
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.
(replacement figure 1)
Structure of a G-quadruplex. Left: a G-tetrad. Right: an
3D Structure of the intramolecular human telomeric
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
1 Quadruplex topology
2 Structure and functional role in genome
3 Telomeric quadruplexes
4 Non-telomeric quadruplexes
5 Quadruplex function
Ligands which bind quadruplexes
7 Quadruplex prediction techniques
8 Role in neurological disorders
9 Therapeutic approaches
12 External links
12.1 Quadruplex websites
12.2 Tools to predict
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.
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.
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. If all
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  . Interstrand
quadruplexes contain guanines that originate from both strands of
Structure and functional role in genome
Following sequencing of the human genome, many guanine-rich sequences
that had the potential to form quadraplexes were discovered.
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. This effect seems to be mediated by alteration of the
hydration of the
DNA and its effect on Hoogsteen base pair
bonding. 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.
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
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. 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
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
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. 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.
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. There are several possible models for how
quadruplexes could influence gene activity, either by upregulation or
downregulation. One model is shown below, with
in or near a promoter blocking transcription of the gene, and hence
de-activating it. In another model, quadruplex formed at the
DNA strand helps to maintain an open conformation of the
DNA strand and enhance an expression of the respective gene.
Model for quadruplex-mediated down-regulation of gene expression
Nucleic acid quadruplexes have been described as "structures in search
of a function", as for many years there was minimal evidence
pointing towards a biological role for these structures. It has been
suggested that quadruplex formation plays a role in immunoglobulin
heavy chain switching. 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
Bloom syndrome protein
Bloom syndrome protein have a high affinity for resolving G4
DNA. 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. The roles of quadruplex structure in translation
control are not as well explored. The direct visualization of
quadruplex structures in human cells has provided an important
confirmation of their existence. 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
DNA structures that protect telomere ends and regulate
Ligands which bind quadruplexes
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. 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
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). 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 and C-strand i-motif formation. Moreover, these
sequences also have the capacity to form slipped and foldback
structures that are implicit intermediates in the formation of both
quadruplex and triplex DNA structures. In one study 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
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
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
G-quadruplex binding proteins, as seen in the
FMR1 gene and Fragile
C9orf72 gene codes for the protein
C9orf72 which is found
throughout the brain in neuronal cytoplasm and at presynaptic
terminals. Mutations of the
C9orf72 gene have been linked to the
development of FTD and ALS. 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. The transcribed
RNA of these repeats have been shown
to form stable G-quadruplexes, with evidence showing that the G4C2
DNA have the ability to form mixed parallel-antiparallel
G-quadruplex structures as well. These
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
Fragile X mental retardation protein (FMRP) is a widely expressed
protein coded by the fragile X mental retardation gene 1 (FMR1) that
G-quadruplex secondary structures in neurons and is involved
in synaptic plasticity. FMRP acts as a negative regulator of
translation, and its binding stabilizes
G-quadruplex structures in
RNA transcripts, inhibiting ribosome elongation of m
RNA in the
neuron's dendrite and controlling the timing of the transcript's
expression. Mutations of this gene can cause the development
of Fragile X Syndrome, autism, and other neurological disorders.
Fragile X Syndrome
Fragile X Syndrome is caused by an increase from 50 to
over 200 CGG repeats within exon 13 of the
FMR1 gene. This repeat
DNA methylation and other epigenetic
heterochromatin modifications of
FMR1 that prevent the transcription
of the gene, leading to pathological low levels of FMRP.
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
C9orf72 (chromosome 9 open reading frame 72).
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
RNA of the
G-quadruplex GGGGCC expansion repeat region, which has lowered the
toxicity in cellular models of C9orf72. 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.
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.  However, a cationic porphyrin known as
TMPyP4 is able to bind to the
C9orf72 GGGGCC repeat region, which
G-quadruplex repeat region to unfold and lose its
interactions with proteins causing it to lose its functionality.
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
Amyotrophic lateral sclerosis
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.
^ Routh, Eric (2017). "A
G-quadruplex DNA-affinity approach for
purification of enzymatically active G4 Resolvase1". J. Vis. Exp. 121.
^ a b Largy, Eric; Mergny, Jean-Louis; Gabelica, Valérie (2016).
"Chapter 7. Role of Alkali Metal Ions in G-Quadruplex Nucleic Acid
Structure and Stability". In Astrid, Sigel; Helmut, Sigel; Roland
K.O., Sigel. The Alkali Metal Ions: Their Role in Life. Metal Ions in
Life Sciences. 16. Springer. pp. 203–258.
^ Sundquist, Wesley; Klug, Aaron (1989). "Telomeric
DNA dimerizes by
formation of guanine tetrads between hairpin loops". Nature. 342
(6251): 825–829. doi:10.1038/342825a0. PMID 2601741.
^ a b Sen, Dipankar; Gilbert, Walter (1988). "Formation of parallel
four-stranded complexes by guanine-rich motifs in
DNA and its
implications for meiosis". Nature. 334 (6180): 364–366.
doi:10.1038/334364a0. PMID 3393228.
^ Han, Haiyong (2000). "
G-quadruplex DNA: a potential target for
anti-cancer drug design". TiPS. 21: 136–142.
doi:10.1016/s0165-6147(00)01457-7 – via Google Scholar.
^ Bochman, Matthew L.; Paeschke, Katrin; Zakian, Virginia A. (2012).
DNA secondary structures: stability and function of G-quadruplex
structures. Nature Reviews Genetics. 13. Nature Publishing Group.
pp. 770–780. doi:10.1038/nrg3296.
^ Rhodes, Daniela; Lipps, Hans J. (2015). "G-quadruplexes and their
regulatory roles in biology". Nucleic Acids Res. 43 (18): 8627–8637.
doi:10.1093/nar/gkv862. PMC 4605312 . PMID 26350216.
^ a b Simonsson, T. (2001). "G-Quadruplex
DNA Structures Variations on
a Theme". Biological Chemistry. 382 (4): 621–628.
doi:10.1515/BC.2001.073. PMID 11405224.
^ Burge, S.; Parkinson, G. N.; Hazel, P.; Todd, A. K.; Neidle, S.
(2006). "Quadruplex DNA: Sequence, topology and structure". Nucleic
Acids Research. 34 (19): 5402–5415. doi:10.1093/nar/gkl655.
PMC 1636468 . PMID 17012276.
^ Cao, K.; Ryvkin, P.; Johnson, FB. (2012). "Computational detection
and analysis of sequences with duplex-derived interstrand G-quadruplex
forming potential". Methods. 57 (1): 3–10.
doi:10.1016/j.ymeth.2012.05.002. PMC 3701776 .
^ Kudlicki, A. (2016). "G-Quadruplexes Involving Both Strands of
DNA Are Highly Abundant and Colocalize with Functional Sites
Human Genome". PLoS ONE. 11 (1): e0146174.
doi:10.1371/journal.pone.0146174. PMC 4699641 .
^ Murat, P.; Balasubramanian, S. (2014). "Existence and consequences
G-quadruplex structures in DNA". Curr. Opin. Genet. Dev. (25):
^ Miyoshi, Daisuke; Karimata, Hisae; Sugimoto, Naoki (May 27, 2006).
Thermodynamics of G-Quadruplex Formation under
Molecular Crowding Conditions". Journal of the American Chemical
Society. 128 (24): 7957–7963. doi:10.1021/ja061267m.
^ Zheng, KW; Chen, Z; Hao, YH; Tan, Z (January 2010). "Molecular
crowding creates an essential environment for the formation of stable
G-quadruplexes in long double-stranded DNA". Nucleic Acids Res. 38
(1): 327–338. doi:10.1093/nar/gkp898.
^ Tamaki, Endoh; Rode, Ambadas B.; Takahashi, Shuntaro; Kataoka, Yuka;
Kuwahara, Masayasu; Sugimoto, Naoki (January 2016). "Real-Time
Monitoring of G-Quadruplex Formation during Transcription". Analytical
Chemistry. 88 (4): 1984–1989.
^ Wang, Q; Liu, J.Q.; Chen, Z; Zheng, K.W.; Chen, C.Y.; Hao, Y.H.;
Tan, Z (2011). "
G-quadruplex formation at the 3' end of telomere DNA
inhibits its extension by telomerase, polymerase and unwinding by
helicase". Nucleic Acids Res. (39): 6229–6237.
^ Schaffitzel, C; Berger, I; Postberg, J; Hanes, J; Lipps, H. J.;
Plückthun, A (2001). "
In vitro generated antibodies specific for
DNA react with Stylonychia lemnae
macronuclei". Proceedings of the National Academy of Sciences. 98
(15): 8572–7. doi:10.1073/pnas.141229498. PMC 37477 .
^ Paeschke, K.; Simonsson, T.; Postberg, J.; Rhodes, D.; Lipps, H. J.
Telomere end-binding proteins control the formation of
DNA structures in vivo". Nature Structural &
Molecular Biology. 12 (10): 847–854. doi:10.1038/nsmb982.
^ Simonsson, T.; Pecinka, P.; Kubista, M. (1998). "
formation in the control region of c-myc". Nucleic Acids Research. 26
(5): 1167–1172. doi:10.1093/nar/26.5.1167. PMC 147388 .
^ Siddiqui-Jain, A.; Grand, C. L.; Bearss, D. J.; Hurley, L. H.
(2002). "Direct evidence for a
G-quadruplex in a promoter region and
its targeting with a small molecule to repress c-MYC transcription".
Proceedings of the National Academy of Sciences. 99 (18):
11593–11598. doi:10.1073/pnas.182256799. PMC 129314 .
^ Huppert, Julian L.; Balasubramanian, Shankar (14 December 2006).
"G-quadruplexes in promoters throughout the human genome". Nucleic
Acids Research. 35 (2): 406–413. doi:10.1093/nar/gkl1057.
^ Dai, Jixun; et al. (5 January 2006). "An
Structure with Mixed Parallel/Antiparallel G-Strands Formed in the
Human BCL-2 Promoter Region in Solution". J. Am. Chem. Soc. 128:
1096–1098. doi:10.1021/ja055636a. CS1 maint: Explicit use of et
^ Fernando, Himesh; et al. (28 May 2006). "A Conserved Quadruplex
Motif Located in a Transcription Activation Site of the
Oncogene". Biochemistry. 45: 7854–7860.
doi:10.1021/bi0601510. CS1 maint: Explicit use of et al. (link)
^ Huppert, J. L.; Balasubramanian, S. (2005). "Prevalence of
quadruplexes in the human genome". Nucleic Acids Research. 33 (9):
2908–2916. doi:10.1093/nar/gki609. PMC 1140081 .
^ Rawal, P.; Kummarasetti, V. B.; Ravindran, J.; Kumar, N.; Halder,
K.; Sharma, R.; Mukerji, M.; Das, S. K.; Chowdhury, S. (2006).
"Genome-wide prediction of G4
DNA as regulatory motifs: Role in
Escherichia coli global regulation".
Genome Research. 16 (5):
644–655. doi:10.1101/gr.4508806. PMC 1457047 .
^ Bugaut A, Balasubramanian S (2012). "5'-UTR
translation regulation and targeting". Nucleic Acids Res. 40 (11):
4727–41. doi:10.1093/nar/gks068. PMC 3367173 .
^ Sen, D.; Gilbert, W. (1988). "Formation of parallel four-stranded
complexes by guanine-rich motifs in
DNA and its implications for
meiosis". Nature. 334 (6180): 364–366. doi:10.1038/334364a0.
^ Kamath-Loeb, A.; Loeb, L. A.; Fry, M. (2012). Cotterill, Sue, ed.
"The Werner Syndrome
Protein is Distinguished from the Bloom Syndrome
Protein by Its Capacity to Tightly Bind Diverse
DNA Structures". PLoS
ONE. 7 (1): e30189. doi:10.1371/journal.pone.0030189.
PMC 3260238 . PMID 22272300.
^ Maizels, N.; Gray, L. T. (2013). Rosenberg, Susan M, ed. "The G4
Genome". PLoS Genetics. 9 (4): e1003468.
doi:10.1371/journal.pgen.1003468. PMC 3630100 .
^ Biffi, G.; Tannahill, D.; McCafferty, J.; Balasubramanian, S.
(2013). "Quantitative visualization of
G-quadruplex structures in
human cells". Nature Chemistry. 5 (3): 182–186.
doi:10.1038/nchem.1548. PMC 3622242 . PMID 23422559.
^ Rice C, Skordalakes E (2016). "Structure and function of the
telomeric CST complex". Computational and Structural Biotechnology
Journal. 14: 161–167. doi:10.1016/j.csbj.2016.04.002.
PMC 4872678 . PMID 27239262.
^ Todd, A. K.; Johnston, M.; Neidle, S. (2005). "Highly prevalent
putative quadruplex sequence motifs in human DNA". Nucleic Acids
Research. 33 (9): 2901–2907. doi:10.1093/nar/gki553.
PMC 1140077 . PMID 15914666.
^ Frank-Kamenetskii, M. D.; Mirkin, S. M (1995). "Triplex DNA
structures". Annual Review of Biochemistry. 64 (9): 65–95.
doi:10.1146/annurev.bi.64.070195.000433. PMID 7574496.
^ Guo, K.; Gokhale, V.; Hurley, L. H.; Sun, D (2008).
G-quadruplex and i-motif structures in the
proximal promoter of the vascular endothelial growth factor gene".
Nucleic Acids Research. 36 (14): 4598–4608. doi:10.1093/nar/gkn380.
PMC 2504309 . PMID 18614607.
^ Sundquist, W. I.; Klug, M. (1989). "Telomeric
DNA dimerizes by
formation of guanine tetrads between hairpin loops". Nature. 342
(6251): 825–829. doi:10.1038/342825a0. PMID 2601741.
^ Mirkin, S. M.; Lyamichev, V. I.; Drushlyak, K. V.; Dobrynin, V. N.;
Filippov, S. A.; Frank-Kamenetskii, M. D. (1987). "
DNA H form requires
a homopurine-homopyrimidine mirror repeat". Nature. 330 (6147):
495–497. doi:10.1038/330495a0. PMID 2825028.
^ Smith, S. S. (2010). "Evolutionary expansion of structurally complex
Cancer Genomics and Proteomics. 7 (4): 207–216.
^ Roberto Simone, Pietro Fratta, Stephen Neidle, Gary N. Parkinson,
Adrian M. Isaacs (May 2015). "G-quadruplexes: Emerging roles in
neurodegenerative diseases and the non-coding transcriptome".
Federation of European Biochemical Societies. 589 (14): 1653–1668.
doi:10.1016/j.febslet.2015.05.003. CS1 maint: Multiple names:
authors list (link)
C9orf72 chromosome 9 open reading frame 72 [Homo sapiens] -
^ Ratnavalli E, Brayne C, Dawson K, Hodges JR (2002). "The prevalence
of frontotemporal dementia". Neurology. 58 (11): 1615–21.
doi:10.1212/WNL.58.11.1615. PMID 12058088.
^ Rutherford NJ, Heckman MG, Dejesus-Hernandez M, Baker MC,
Soto-Ortolaza AI, Rayaprolu S, Stewart H, Finger E, Volkening K,
Seeley WW, Hatanpaa KJ, Lomen-Hoerth C, Kertesz A, Bigio EH, Lippa C,
Knopman DS, Kretzschmar HA, Neumann M, Caselli RJ, White CL 3rd,
Mackenzie IR, Petersen RC, Strong MJ, Miller BL, Boeve BF, Uitti RJ,
Boylan KB, Wszolek ZK, Graff-Radford NR, Dickson DW, Ross OA,
Rademakers R. (Dec 2012). "Length of normal alleles of C9ORF72 GGGGCC
repeat do not influence disease phenotype". Neurobiology of Aging. 33
(12): 2950.e5–7. doi:10.1016/j.neurobiolaging.2012.07.005.
PMC 3617405 . PMID 22840558. CS1 maint: Multiple
names: authors list (link)
^ Jon Beck, Mark Poulter, Davina Hensman, Jonathan D. Rohrer, Colin J.
Mahoney, Gary Adamson, Tracy Campbell, James Uphill, Aaron Borg,
Pietro Fratta, Richard W. Orrell, Andrea Malaspina, James Rowe, Jeremy
Brown, John Hodges, Katie Sidle, James M. Polke, Henry Houlden,
Jonathan M. Schott, Nick C. Fox, Martin N. Rossor, Sarah J. Tabrizi,
Adrian M. Isaacs, John Hardy, Jason D. Warren, John Collinge, and
Simon Mead (March 2013). "Large
C9orf72 Hexanucleotide Repeat
Expansions Are Seen in Multiple Neurodegenerative Syndromes and Are
More Frequent Than Expected in the UK Population". The American
Human Genetics. 92 (3): 345–353.
doi:10.1016/j.ajhg.2013.01.011. CS1 maint: Multiple names:
authors list (link)
^ Pietro Fratta, Sarah Mizielinska, Andrew J. Nicoll, Mire Zloh,
Elizabeth M. C. Fisher, Gary Parkinson, and Adrian M. Isaacs (December
C9orf72 hexanucleotide repeat associated with amyotrophic
lateral sclerosis and frontotemporal dementia forms RNA
G-quadruplexes". Scientific Reports. 2: 1016.
doi:10.1038/srep01016. CS1 maint: Multiple names: authors list
^ Kaalak Reddy, Bita Zamiri, Sabrina Y. R. Stanley, Robert B.
Macgregor Jr. and Christopher E. Pearson (April 2013). "The
Disease-associated r(GGGGCC)n Repeat from the
Gene Forms Tract
Length-dependent Uni- and Multimolecular
Journal of Biological Chemistry. 288 (14): 9860–9866.
doi:10.1074/jbc.C113.452532. CS1 maint: Multiple names: authors
^ Aaron R. Haeusler, Christopher J. Donnelly, Goran Periz, Eric A. J.
Simko, Patrick G. Shaw, Min-Sik Kim, Nicholas J. Maragakis, Juan C.
Troncoso, Akhilesh Pandey, Rita Sattler, Jeffrey D. Rothstein &
Jiou Wang (March 2014). "
C9orf72 nucleotide repeat structures initiate
molecular cascades of disease". Nature. 507: 195–200.
doi:10.1038/nature13124. CS1 maint: Multiple names: authors list
^ Darnell, J. C., Jensen, K. B., Jin, P., Brown, V., Warren, S. T.,
Darnell. R. B. (November 2001). "Fragile X Mental Retardation Protein
Targets G Quartet mRNAs Important for Neuronal Function". Cell. 107
(4): 489–499. doi:10.1016/S0092-8674(01)00566-9. CS1 maint:
Multiple names: authors list (link)
^ Ceman, S., O'Donnell, W. T., Reed, M., Patton, S., Pohl, J., Warren,
S. T. (December 2003). "Phosphorylation influences the translation
state of FMRP-associated polyribosomes".
Human Molecular Genetics. 12
(24): 3295–3305. doi:10.1093/hmg/ddg350. CS1 maint: Multiple
names: authors list (link)
^ Fahling, M., Mrowka, R., Steege, A., Kirschner, K. M., Benko, E.,
Forstera, B., Persson, P. B., Thiele, B. J., Meier, J. C., Scholz, H.
(Dec 2008). "Translational Regulation of the
Homologue-1 by Fragile X Mental Retardation Protein". Journal of
Biological Chemistry. 284: 4255–4266.
doi:10.1074/jbc.M807354200. CS1 maint: Multiple names: authors
^ "Fragile X Mental Retardation" The
^ Pieretti, M., Zhang, F., Fu, Y., Warren, S. T., Oostra, B. A.,
Caskey, C. T., Nelson, D. L. (August 1991). "Absence of expression of
the FMR-1 gene in fragile X syndrome". Cell. 66 (4): 816–822.
doi:10.1016/0092-8674(91)90125-I. CS1 maint: Multiple names:
authors list (link)
^ Sutcliffe, J. S., Nelson, D. L., Zhang, F., Pieretti, M., Caskey, C.
T., Saxe, D., Warren, S. T. (September 1992). "
represses FMR-1 transcription in fragile X syndrome".
Genetics. 1 (6): 397–400. doi:10.1093/hmg/1.6.397. CS1 maint:
Multiple names: authors list (link)
^ Mizielinska, S., Isaacs, A.M. (2014).
C9orf72 amyotrophic lateral
sclerosis and frontotemporal dementia: gain or loss of function? Curr.
Opin. Neurol. 27. 515-523.
^ Donnelly, C.J., Zhang, P.W., et. al. (2013).
RNA toxicity from the
C9orf72 expansion is mitigated by antisense intervention.
Neuron. 80. 415-428.
^ Lagier-Tourenne, C., Baughn, M., et. al. (2013). Targeted
degradation of sense and antisense
C9orf72 foci as therapy for ALS and
frontotemporal degeneration. Proc. Natl. Acad. Sci. U.S.A. 110.
^ Sareen, D., O’Rourke, J.G., et. al. (2013) Targeting
RNA foci in
iPSC-derived motor neurons from ALS patients with
expansion. Sci. Transl. Med. 5. 208ra149.
^ Wheeler, T.M., Leger, A.J., et. al. (2012). Targeting nuclear RNA
for in vivo correction of myotonic dystrophy. Nature. 488. 111-115.
^ Lee, J.E., Bennett, C.F., and Cooper, T.A. (2012). RNAse H-mediated
degradation of toxic
RNA in myotonic dystrophy type 1. Proc. Natl.
Acad. Sci. U.S.A. 109. 4221-4226.
^ Carroll, J.B., Warby., S.C., et. al. (2011). Potent and selective
antisense oligonucleotides targeting single nucleotide polymorphisms
in the Huntington disease gene/allele-specific silencing of mutant
Huntingtin. Mol. Ther. 19. 2178-2185.
^ Gagnen, K.T., Pendergraff, H.M. (2010). Allele-selective inhibition
of mutant huntingtin expression with antisense oligonucleotides
targeting the expanded CAG repeat. Biochem. 49. 10166-10178.
^ Campbell, N.H., Patel, M., et al. (2009). Selective in ligand
G-quadruplex loops. Biochem. 48. 1675-1680.
^ Ohnmacht, S.A., and Neidle, S. (2014). Small-molecule quadruplex
targeted drug discovery. Bioorg. Med. Chem. Lett. 24. 2602-2612.
^ Zamiri, B., Reddy, K., et. al. (2014). TMPyP4 porphyrin distorts RNA
G-quadruplex structures of the disease associated r(GGGGCC)n repeat of
C9orf72 gene and blocks interactions of RNA-binding proteins. J.
Biol. Chem. 289. 4653-4659.
^ Vilar, Ramon (2018). "Chapter 12. Nucleic Acid Quadruplexes and
Metallo-Drugs". In Sigel, Astrid; Sigel, Helmut; Freisinger, Eva;
Sigel, Roland K. O. Metallo-Drugs: Development and Action of
Anticancer Agents. 18. Berlin: de Gruyter GmbH. pp. 325–349.
Jiangtao Ren; Jiahai Wang*; Lei Han; Erkang Wang*; Jin Wang* (2011).
"Kinetically grafting G-qaudruplex onto
DNA nanostructure as structure
and function encoding via
DNA machine". Chem. Commun. 47 (38):
Johnson JE, Smith JS, Kozak ML, Johnson FB (2008). "
In vivo veritas:
using yeast to probe the biological functions of G-quadruplexes".
Biochimie. 90 (8): 1250–1263. doi:10.1016/j.biochi.2008.02.013.
PMC 2585026 . PMID 18331848.
Huppert JL, Balasubramanian S (2005). "Prevalence of quadruplexes in
the human genome". Nucleic Acids Research. 33 (9): 2908–2916.
doi:10.1093/nar/gki609. PMC 1140081 . PMID 15914667.
Todd AK, Johnston M, Neidle S (2005). "Highly prevalent putative
quadruplex sequence motifs in human DNA". Nucleic Acids Research. 33
(9): 2901–2907. doi:10.1093/nar/gki553. PMC 1140077 .
Burge S, Parkinson GN, Hazel P, Todd AK, Neidle S (2006). "Quadruplex
DNA: sequence, topology and structure". Nucleic Acids Research. 34
(19): 5402–5415. doi:10.1093/nar/gkl655. PMC 1636468 .
Siddiqui-Jain A, Grand CL, Bearss DJ, Hurley LH (2002). "Direct
evidence for a
G-quadruplex in a promoter region and its targeting
with a small molecule to repress c-MYC transcription". PNAS. 99 (18):
11593–8. doi:10.1073/pnas.182256799. PMC 129314 .
Rawal P, Kummarasetti VB, Ravindran J, Kumar N, Halder K, Sharma R,
Mukerji M, Das SK, Chowdhury S (2006). "Genome-wide prediction of G4
DNA as regulatory motifs: Role in Escherichia coli global regulation".
Genome Res. 16 (5): 644–55. doi:10.1101/gr.4508806.
PMC 1457047 . PMID 16651665.
Xu Hou; Wei Guo; Fan Xia; Fu-Qiang Nie; Hua Dong; Ye Tian; Liping Wen;
Lin Wang; Liuxuan Cao; Yang Yang; Jianming Xue; Yanlin Song; Yugang
Wang; Dongsheng Liu; Lei Jiang (2009). "A biomimetic potassium
DNA conformational switching in a
synthetic nanopore". J. Am. Chem. Soc. 131 (22): 7800–7805.
doi:10.1021/ja901574c. PMID 19435350.
Neidle & Balasubramanian, ed. (2006). Quadruplex Nucleic Acids.
ISBN 0-85404-374-8. Archived from the original on
Rowland, Gerald B.; Barnett, Kerry; DuPont, Jesse I.; Akurathi,
Gopalakrishna; Le, Vu H.; Lewis, Edwin A (1 December 2013). "The
effect of pyridyl substituents on the thermodynamics of porphyrin
G-quadruplex DNA". Bioorganic & Medicinal Chemistry. 21
(23): 7515–. doi:10.1016/j.bmc.2013.09.036.
Nanopore and Aptamer Biosensor group NAB group
G-Quadruplex World – a website to discuss publications and other
information of interest to those working in the field of
Quadbase – downloadable data on predicted G-quadruplexes
Greglist – a database listing potential
G-quadruplex regulated genes
Database on Quadruplex information: QuadBase from IGIB
GRSDB- a database of G-quadruplexes near
RNA processing sites.
GRS_UTRdb- a database of G-quadruplexes in the UTRs.
G-quadruplex Resource Site
non-B Motif Search Tool at non-B DB- a web server to predict
G-quadruplex forming motifs and other non-B
DNA forming motifs from
Tools to predict
Quadparser: Downloadable program for finding putative
quadruplex-forming sequences from Balasubramanian's group.
QGRS Mapper: a web-based application for predicting G-quadruplexes in
nucleotide sequences and NCBI genes from Bagga's group.
Quadfinder: Tool for Prediction and Analysis of G Quadruplex Motifs in
RNA Sequences from Maiti's group, IGIB, Delhi, India[permanent
 G4Hunter from Mergny's group but user need to run the code in R.
 pqsfinder: an exhaustive and imperfection-tolerant search tool for