G-quadruplex - Knowledge

991:; 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 perfectly 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 causes the 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 with 413:, has also been identified as a key G-quadruplex resolvase. In 2009, a metastasis suppressor protein NM23H2 (also known as NME2) was found to directly interact with G-quadruplex in the promoter of the c-myc gene, and transcriptionally regulate c-myc. More recently, NM23H2 was reported to interact with G-quadruplex in the promoter of the human telomerase (hTERT) gene and regulate hTERT expression In 2019, the telomere-binding-factor-2 (TRF2 or TERF2) was shown to bind to thousands of non-telomeric G-quadruplexes in the human genome by TRF2 ChIP-seq. There are many studies that implicate quadruplexes in both positive and negative transcriptional regulation, including epigenetic regulation of genes like hTERT. Function of G-quadruplexes have also been reported in allowing programmed recombination of immunologlobin heavy genes and the pilin 292:. Analysis of human, chimpanzee, mouse and rat genomes showed enormous number of potential G-quadruplex (pG4)-forming sequences in non-telomeric regions. A large number of the non-telomeric G-quadruplexes were found within gene promoters, and were conserved across the species. Similarly, large number of G-quadruplexes were found in the E. coli and hundreds of other microbial genomes. Here also, like vertebrates G-quadruplexes were enriched within gene promoters. In addition, there was found more than one-billion-year conserved G-quadruplex locus in plants and algae, in gene encoding large subunit of RNA polymerase II. Although these studies predicted G-quadruplex-mediated gene regulation, it is unlikely that all pG4s would form in vivo. The 162:. 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. 130:, these structures hold a biologically relevant role through interactions with the promoter regions of oncogenes and the telomeric regions of DNA strands. Current research consists of identifying the biological function of these G-Quadruplex structures for specific oncogenes and discovering effective therapeutic treatments for cancer based on interactions with G-quadruplexes. Early evidence for the formation of G-quadruplexes in vivo in cells was established by isolating them from cells, and later by the observation that specific DNA helicases could be identified where small molecules specific for these DNA structures accumulated in cells. 798:

these signals at 262 and 295 nm, respectively. To verify G-quadruplex formation, one should also perform the CD experiments under non-G-quadruplex stabilizing (Li+) and G-quadruplex stabilizing conditions (such as K+ or with G-quadruplex ligands), and scan toward the far-UV region (180–230 nm). Likewise, the thermostability of the G-quadruplex structure can be identified by observing the UV signal at 295 nm. Upon G-quadruplex melting, the UV absorbance at 295 nm decreases, leading to a hypochromic shift that is a distinctive feature of G-quadruplex structure. Another approach for detection of G-quadruplexes includes

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behind the loading of these TFs, where APE1 dissociates from the G-quadruplex structures. When a study downregulated the presence of APE1 and AcAPE1 in the cell, the formation of G-quadruplex structures was inhibited, which proves the importance of APE1 for the formation of these structures. However, not all G-quadruplex structures require APE1 for formation, in fact some of them formed greater G-quadruplex structures in its absence. Therefore, we can conclude that APE1 has two important roles in genome regulation- Stabilizing the formation of g-quadruplex structures and loading the transcriptional factors onto the AP site

453:(BER). Base excision repair processes in cells have been proved to be reduced with aging as its components in the mitochondria begin to decline, which can lead to the formation of many diseases such as Alzheimer's disease (AD). These G-quadruplex structures are said to be formed in the promoter regions of DNA through superhelicity, which favors the unwinding of the double helical structure of DNA and in turn loops the strands to form G-quadruplex structures in guanine rich regions. The BER pathway is signalled when it indicates an oxidative DNA base damage, where structures like, 166:

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.

423:. The roles of quadruplex structure in translation control are not as well explored. The direct visualization of G-quadruplex structures in human cells as well as the co-crystal structure of an RNA helicase bound to a G-quadruplex 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. 763:. 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 542:

G-quadruplex structures in that region. This promotes formation of G-quadruplex structures by the folding of the stand. This looping process brings four bases in close proximity that will be held together by Hoogsteen base pairing. After this stage the APE1 gets acetylated by multiple lysine residues on the chromatin, forming acetylated APE1 (AcAPE1). AcAPE1 is very crucial to the BER pathway as it acts as a transcriptional coactivator or corepressor, functioning to load

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regions to inhibit the production of both the c-Myc protein product and the human telomerase reverse transcriptase (hTERT). This main pathway of targeting this region results in the lack of telomerase elongation, leading to arrested cell development. Further research remains necessary for the discovery of a single gene target to minimize unwanted reactivity with more efficient antitumor activity.

38:. They are helical in shape and contain 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, both in microbes and across vertebrates including oncogenes in humans. Four guanine bases can associate through 614:

through the abundant guanine sequence in the promoter region of this specific pathway. The cyclin-dependent cell cycle checkpoint kinase inhibitor-1 CDKN1A (also known as p21) gene harbours promoter G-quadruplex. Interaction of this G-quadruplex with TRF2 (also known as TERF2) resulted in epigenetic regulation of p21, which was tested using the G-quadruplex-binding ligand 360A.

621:. Through recent research into this specific gene pathway, the polypurine and polypyrimidine region allows for the transcription of this specific gene and the formation of an intramolecular G-quadruplex structure. However, more research is necessary to determine whether the formation of G-quadruplex regulates the expression of this gene in a positive or negative manner. 89:. 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. 637:

the promoter region of PDGF-A has exhibited the ability to form intramolecular parallel G-quadruplex structures and remains suggested to play a role in transcriptional regulation of PDGF-A. However, research has also identified the presence of G-quadruplex structures within this region due to the interaction of TMPyP4 with this promoter sequence.

568:. However, in cancer cells that have mutated helicase these complexes cannot be unwound and leads to potential damage of the cell. This causes replication of damaged and cancerous cells. For therapeutic advances, stabilizing the G-quadruplexes of cancerous cells can inhibit cell growth and replication leading to the 714:. Furthermore, the hydrogen bonds of ligands with smaller side chains are shorter and therefore stronger. Ligands with mobile side chains, ones that are able to rotate around its center chromophore, associate more strongly to G-quadruplexes because conformation of the G4 loops and the ligand side chains can align. 653:

Ligand design and development remains an important field of research into therapeutic reagents due to the abundance of G-quadruplexes and their multiple conformational differences. One type of ligand involving a Quindoline derivative, SYUIQ-05, utilizes the stabilization of G-quadruplexes in promoter

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Another oncogene pathway involving PDGF-A, platelet-derived growth factor, involves the process of wound healing and function as mitogenic growth factors for cells. High levels of expression of PDGF have been associated with increased cell growth and cancer. The presence of a guanine-rich sequence in

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AP endonuclease 1 (APE1) is an enzyme responsible for the promotion and the formation of G-quadruplex structures. APE1 is mainly in charge of repairing damage caused to AP sites through the BER pathway. APE1 is considered to be very crucial as AP site damage is known to be the most recurring type of

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does so by cleaving the oxidized base and thus creating an AP site, primarily through the process of negative superhelicity. This AP site then signals cells to engage APE1 binding, which binds to the open duplex region. The binding of APE1 then plays an important role by stabilizing the formation of

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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

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into the site of damage allowing it to regulate the gene expression. AcAPE1 is also very important since it allows APE1 to bind for longer periods of time by delay of its dissociation from the sequence, allowing the repair process to be more efficient. Deacetylation of AcAPE1 is the driving force

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and ARP, have indicated that AP site damage occurrence is nonrandom. AP site damage was also more prevalent in certain regions of the genome that contain specific active promoter and enhancer markers, some of which were linked to regions responsible for lung adenocarcinoma and colon cancer. AP site

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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, Mackenzie IR, Petersen RC, Strong MJ, Miller

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The topology of the G-quadruplex structure can be determined by monitoring the positive or negative circular dichroism (CD) signals at specific wavelengths. Parallel G-quadruplexes have negative and positive CD signals at 240 and 262 nm, respectively, whereas antiparallel G-quadruplexes place

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of the VEGF gene. Through recent research on the role of G-quadruplex function in vivo, the stabilization of G-quadruplex structures was shown to regulate VEGF gene transcription, with inhibition of transcription factors in this pathway. The intramolecular G-quadruplex structures are formed mostly

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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

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Biochemical techniques were employed to interrogate G-quadruplex formation in a longer sequence context. In the DNA polymerase stop assay, the formation of a G-quadruplex in a DNA template can act as a roadblock and cause polymerase stalling, which halts the primer extension. The dimethyl sulfate

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which makes them effective anticancer agents. However, TMPyP4 has been limited for used due to its non-selectivity toward cancer cell telomeres and normal double stranded DNA (dsDNA). To address this issue analog of TMPyP4, it was synthesized known as 5Me which targets only G quadruplex DNA which

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which has been abundant in certain types of cancer. The guanine rich sequence in the promoter region for this pathway exudes a necessity for baseline transcription of this receptor tyrosine kinase. In certain types of cancers, the RET protein has shown increased expression levels. The research on

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and VEGF, showing the importance of this secondary structure in cancer growth and development. While the formation of G-quadruplex structure vary to some extent for the different promoter regions of oncogenes, the consistent stabilization of these structures have been found in cancer development.

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function of G-quadruplexes surged after large scale genome-wide analysis showed the prevalence of potential G-quadruplex (pG4)-forming sequences within gene promoters of human, chimpanzee, mouse, and rat - presented in the First International G-quadruplex Meeting held in April 2007 in Louisville,

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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,

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Furthermore, the concentration of 8-oxo-dG is a known biomarker of oxidative stress within a cell, and excessive amount of oxidative stress has been linked to carcinogenesis and other diseases. When produced, 8-oxo-dG, has the ability to inactivate OGG1, thus preventing the repair of DNA damage

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Lagier-Tourenne C, Baughn M, Rigo F, Sun S, Liu P, Li HR, Jiang J, Watt AT, Chun S, Katz M, Qiu J, Sun Y, Ling SC, Zhu Q, Polymenidou M, Drenner K, Artates JW, McAlonis-Downes M, Markmiller S, Hutt KR, Pizzo DP, Cady J, Harms MB, Baloh RH, Vandenberg SR, Yeo GW, Fu XD, Bennett CF, Cleveland DW,

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Another gene pathway deals with the VEGF gene, Vascular Endothelial Growth Factor, which remains involved in the process of angiogenesis or the formation of new blood vessels. The formation of an intramolecular G-quadruplex structure has been shown through studies on the polypurine tract of the

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The c-kit oncogene deals with a pathway that encodes an RTK, which was shown to have elevated expression levels in certain types of cancer. The rich guanine sequence of this promoter region has shown the ability to form a variety of quadruplexes. Current research on this pathway is focusing on

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Regulation of c-myc through Human telomerase reverse transcriptase (hTERT) is also directly regulated through promoter G-quadruplex by interaction with the transcription factor NM23H2 where epigenetic modifications were dependent on NM23H2-G-quadruplex association. Recently, hTERT epigenetic

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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 strands of DNA proceed in the same direction, the quadruplex is termed parallel. For

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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-quadruplexes if the overhang is longer than four TTAGGG repeats. The presence of these structures prevent telomere elongation by the telomerase complex.

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that mimic the G-quadruplex structure and compete with the endogenous G-quadruplexes for binding to transcription factors. These decoys are typically composed of a G-rich sequence that can form a stable G-quadruplex structure and a short linker region that can be modified to optimize their

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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.

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to bind and remove the oxidative damage with the help of APE1, resulting in an AP site. Moreover, an AP site is a location in DNA that has neither a purine or a pyrimidine base due to DNA damage, they are the most prevalent type of endogenous DNA damage in cells. AP sites can be generated

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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

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A new technique to map AP sites has been developed known as AP-seq which utilizes a biotin-labeled aldehyde-reactive probe (ARP) to tag certain regions of the genome where AP site damage occurrence has been significant. Another genome-wide mapping sequencing method known as

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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

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One particular gene region, the c-myc pathway, plays an integral role in the regulation of a protein product, c-Myc. With this product, the c-Myc protein functions in the processes of apoptosis and cell growth or development and as a transcriptional control on human

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When designing ligands to be bound to G-quadruplexes, the ligands have a higher affinity for parallel folded G-quadruplexes. It has been found that ligands with smaller side chains bind better to the quadruplex because smaller ligands have more concentrated

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3D Structure of the intramolecular human telomeric G-quadruplex in potassium solution. 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.

789:(DMS) followed by the piperidine cleavage assay is based on the fact that the formation of a G-quadruplex will prohibit the N7 guanine methylation caused by DMS, leading to a protection pattern observed at the DNA G-quadruplex region after piperidine cleavage. 771:

More recently, advanced web-based toolboxes for identifying G-quadruplex forming sequences were developed, including user-friendly and open access version of G4Hunter based on sliding window approach or G4RNA Screener based on machine learning algorithm.

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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.

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endogenous damage to DNA. The oxidation of certain purine bases, like guanine, forms oxidized nucleotides that impairs DNA function by mismatching nucleotides in the sequences. This is more common in PQS sequences which form oxidized structures, such as

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Donnelly CJ, Zhang PW, Pham JT, Haeusler AR, Heusler AR, Mistry NA, Vidensky S, Daley EL, Poth EM, Hoover B, Fines DM, Maragakis N, Tienari PJ, Petrucelli L, Traynor BJ, Wang J, Rigo F, Bennett CF, Blackshaw S, Sattler R, Rothstein JD (October 2013).

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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:

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Chilakamarthi U, Koteshwar D, Jinka S, Vamsi Krishna N, Sridharan K, Nagesh N, Giribabu L (November 2018). "Novel Amphiphilic G-Quadruplex Binding Synthetic Derivative of TMPyP4 and Its Effect on Cancer Cell Proliferation and Apoptosis Induction".

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Cogoi S, Paramasivam M, Filichev V, Géci I, Pedersen EB, Xodo LE (January 2009). "Identification of a new G-quadruplex motif in the KRAS promoter and design of pyrene-modified G4-decoys with antiproliferative activity in pancreatic cancer cells".

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Verma A, Halder K, Halder R, Yadav VK, Rawal P, Thakur RK, Mohd F, Sharma A, Chowdhury S (2008). "Genome-wide Computational and Expression Analyses Reveal G-quadruplex DNA Motifs as Conserved Cis-Regulatory Elements in Human and Related Species".

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Hou X, Guo W, Xia F, Nie FQ, Dong H, Tian Y, Wen L, Wang L, Cao L, Yang Y, Xue J, Song Y, Wang Y, Liu D, Jiang L (June 2009). "A biomimetic potassium responsive nanochannel: G-quadruplex DNA conformational switching in a synthetic nanopore".

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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

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holding it together. When bound, MM41's central chromophore is situated on top of the 3’ terminal G-quartet and the side chains of the ligand associate to the loops of the quadruplex. The quartet and the chromophore are bound with a

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Ou TM, Lin J, Lu YJ, Hou JQ, Tan JH, Chen SH, Li Z, Li YP, Li D, Gu LQ, Huang ZS (August 2011). "Inhibition of cell proliferation by quindoline derivative (SYUIQ-05) through its preferential interaction with c-myc promoter G-quadruplex".

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caused by the oxidation of guanine. The possible inactivation allows for un-repaired DNA damages to gather in non-replicating cells, like muscle, and can cause aging as well. Moreover, oxidative DNA damage like 8-oxo-dG contributes to

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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.

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Sareen D, O'Rourke JG, Meera P, Muhammad AK, Grant S, Simpkinson M, Bell S, Carmona S, Ornelas L, Sahabian A, Gendron T, Petrucelli L, Baughn M, Ravits J, Harms MB, Rigo F, Bennett CF, Otis TS, Svendsen CN, Baloh RH (October 2013).

995:(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. 4428:

Hussain T, Saha D, Purohit G, Mukherjee AK, Sharma S, Sengupta S, Dhapola P, Maji B, Vedagopuram S, Horikoshi NT, Horikoshi N, Pandita RK, Bhattacharya S, Bajaj A, Riou JF, Pandita TK, Chowdhury S (September 2017).

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spontaneously or after the cleavage of modified bases, like 8-OH-Gua. The generation of an AP site enables the melting of the duplex DNA to unmask the PQS, adopting a G-quadruplex fold. With the use of genome-wide

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Rodriguez, Raphaël; Miller, Kyle M; Forment, Josep V; Bradshaw, Charles R; Nikan, Mehran; Britton, Sébastien; Oelschlaegel, Tobias; Xhemalce, Blerta; Balasubramanian, Shankar; Jackson, Stephen P (5 February 2012).

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The binding of ligands to G-quadruplexes is vital for anti-cancer pursuits because G-quadruplexes are found typically at translocation hot spots. MM41, a ligand that binds selectively for a quadruplex on the

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De Armond R, Wood S, Sun D, Hurley LH, Ebbinghaus SW (December 2005). "Evidence for the presence of a guanine quadruplex forming region within a polypurine tract of the hypoxia inducible factor 1alpha promoter".

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promoter, is shaped with a central core and 4 side chains branching sterically out. The shape of the ligand is vital because it closely matches the quadruplex which has stacked quartets and the loops of

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Beck J, Poulter M, Hensman D, Rohrer JD, Mahoney CJ, Adamson G, Campbell T, Uphill J, Borg A, Fratta P, Orrell RW, Malaspina A, Rowe J, Brown J, Hodges J, Sidle K, Polke JM, Houlden H, Schott JM, Fox NC,

4381:"Facilitation of a structural transition in the polypurine/polypyrimidine tract within the proximal promoter region of the human VEGF gene by the presence of potassium and G-quadruplex-interactive agents" 469:

Guanine (G) bases in G-quadruplex have the lowest redox potential causing it to be more susceptible to the formation of 8-oxoguanine (8-oxoG), an endogenous oxidized DNA base damage in the genome. Due to

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Kentucky. In 2006, the prevalence of G-quadruplexes within gene promoters of several bacterial genomes was reported predicting G-quadruplex-mediated gene regulation. With the abundance of G-quadruplexes

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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.

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within a cell. When DNA undergoes oxidative damage, a possible structural change in guanine, after ionizing radiation, gives rise to an enol form, 8-OH-Gua. This oxidative product is formed through a

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Many of the genome regulatory processes have been linked to the formation of G-quadruplex structures, attributable to the huge role it plays in DNA repair of apurinic/apyrimidinic sites also known as

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while the side chains and loops are not bound but are in close proximity. What makes this binding strong is the fluidity in the position of the loops to better associate with the ligand side chains.

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The G-quadruplex decoy strategy is another promising approach for targeting cancer cells by exploiting the unique structural features of the G-quadruplex. The strategy involves designing synthetic

254:) consists of many repeats of the sequenced (TTAGGG), and the quadruplexes formed by this structure can be in bead-like structures of 5 nm to 8 nm in size and have been well studied by 588:

promoter regions. The structures most present in the promoter regions of these oncogenes tend to be parallel-stranded G-quadruplex DNA structures. Some of these oncogenes include c-KIT, PDGF-A,

3647:"The importance of negative superhelicity in inducing the formation of G-quadruplex and i-motif structures in the c-Myc promoter: implications for drug targeting and control of gene expression" 169:

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

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cells, especially in telomeres, 5` untranslated strands, and translocation hot spots. G-quadruplexes can inhibit normal cell function, and in healthy cells, are easily and readily unwound by

670:, 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. 512:

through the modulation of gene expression, or the induction of mutations. On the condition that 8-oxo-dG is repaired by BER, parts of the repair protein is left behind which can lead to

987:. 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 4664:

Ohnmacht SA, Marchetti C, Gunaratnam M, Besser RJ, Haider SM, Di Vita G, Lowe HL, Mellinas-Gomez M, Diocou S, Robson M, Šponer J, Islam B, Pedley RB, Hartley JA, Neidle S (June 2015).

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association became apparent in the early 1960s, through the identification of gel-like substances associated with guanines. More specifically, this research detailed the four-stranded

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Henderson E, Hardin CC, Walk SK, Tinoco I, Blackburn EH (December 1987). "Telomeric DNA oligonucleotides form novel intramolecular structures containing guanine-guanine base pairs".

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Rowland GB, Barnett K, Dupont JI, Akurathi G, Le VH, Lewis EA (December 2013). "The effect of pyridyl substituents on the thermodynamics of porphyrin binding to G-quadruplex DNA".

181:, many guanine-rich sequences that had the potential to form quadruplexes were discovered. Depending on cell type and cell cycle, mediating factors such as DNA-binding proteins on 617:

Hypoxia inducible factor 1ɑ, HIF-1ɑ, remains involved in cancer signaling through its binding to Hypoxia Response Element, HRE, in the presence of hypoxia to begin the process of

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Gagnon KT, Pendergraff HM, Deleavey GF, Swayze EE, Potier P, Randolph J, Roesch EB, Chattopadhyaya J, Damha MJ, Bennett CF, Montaillier C, Lemaitre M, Corey DR (November 2010).

6529:"MAZ-binding G4-decoy with locked nucleic acid and twisted intercalating nucleic acid modifications suppresses KRAS in pancreatic cancer cells and delays tumor growth in mice" 912:

Fragile X mental retardation protein (FMRP) is a widely expressed protein coded by the FMR1 gene that binds to G-quadruplex secondary structures in neurons and is involved in

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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

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The placement and bonding to form G-quadruplexes is not random and serve very unusual functional purposes. The quadruplex structure is further stabilized by the presence of a

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analyses, cell-based assays, and in vitro biochemical analyses, a connection has been made between oxidized DNA base-derived AP sites, and the formation of the G-quadruplex.

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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

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A number of experimental methods have been developed to identify G-quadruplexes. These methods can be broadly defined into two classes: biophysical and biochemical methods.

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Largy E, Mergny J, Gabelica V (2016). "Chapter 7. Role of Alkali Metal Ions in G-Quadruplex Nucleic Acid Structure and Stability". In Astrid S, Helmut S, Roland KO (eds.).

6395:"Potent and selective antisense oligonucleotides targeting single-nucleotide polymorphisms in the Huntington disease gene / allele-specific silencing of mutant huntingtin" 158:

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

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Ren J, Wang J, Han L, Wang E, Wang J (October 2011). "Kinetically grafting G-quadruplexes onto DNA nanostructures for structure and function encoding via a DNA machine".

6648:"TMPyP4 porphyrin distorts RNA G-quadruplex structures of the disease-associated r(GGGGCC)n repeat of the C9orf72 gene and blocks interaction of RNA-binding proteins" 2349:

Paeschke K, Simonsson T, Postberg J, Rhodes D, Lipps HJ (October 2005). "Telomere end-binding proteins control the formation of G-quadruplex DNA structures in vivo".

706: The way in which TMPyP4 binds to G4's is similar to MM41, with the ring stacking onto the external G-quartet and side chains associating to the loops of G4's. 6033:

Sutcliffe JS, Nelson DL, Zhang F, Pieretti M, Caskey CT, Saxe D, Warren ST (September 1992). "DNA methylation represses FMR-1 transcription in fragile X syndrome".

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Sun D, Hurley LH (2009-10-23). "Biochemical Techniques for the Characterization of G-Quadruplex Structures: EMSA, DMS Footprinting, and DNA Polymerase Stop Assay".

625:

discovering the biological function of this specific quadruplex formation on the c-kit pathway, while this quadruplex sequence has been noticed in various species.

4573:"Characterization of the G-quadruplexes in the duplex nuclease hypersensitive element of the PDGF-A promoter and modulation of PDGF-A promoter activity by TMPyP4" 645:

Telomeres are generally made up of G-quadruplexes and remain important targets for therapeutic research and discoveries. These complexes have a high affinity for

807: 449:

damage was found to be predominant in PQS regions of the genome, where formation of G-quadruplex structures is regulated and promoted by the DNA repair process,

4952:

Mirkin SM, Lyamichev VI, Drushlyak KN, Dobrynin VN, Filippov SA, Frank-Kamenetskii MD (1987). "DNA H form requires a homopurine-homopyrimidine mirror repeat".

803: 520:

gene of humans, it was determine that if 8-oxo-dG was left unchecked and not repaired by BER, it can lead to frequent mutations and eventually carcinogenesis.

46:(G-tetrad or G-quartet), and two or more guanine tetrads (from G-tracts, continuous runs of guanine) can stack on top of each other to form a G-quadruplex. 5629:"Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population" 5276:

Paramasivan S, Rujan I, Bolton PH (December 2007). "Circular dichroism of quadruplex DNAs: applications to structure, cation effects and ligand binding".

109:

regions of DNA in the 1980s. The importance of discovering G-quadruplex structure was described through the statement, “If G-quadruplexes form so readily

3842:"8-Oxo-7,8-dihydro-2'-deoxyguanosine and abasic site tandem lesions are oxidation prone yielding hydantoin products that strongly destabilize duplex DNA" 593:

Current therapeutic research actively focuses on targeting this stabilization of G-quadruplex structures to arrest unregulated cell growth and division.

5990:

Pieretti M, Zhang FP, Fu YH, Warren ST, Oostra BA, Caskey CT, Nelson DL (August 1991). "Absence of expression of the FMR-1 gene in fragile X syndrome".

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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 (G

189:

proteins, and other environmental conditions and stresses affect the dynamic formation of quadruplexes. For instance, quantitative assessments of the

5030:

Brázda, Václav; Kolomazník, Jan; Lýsek, Jiří; Bartas, Martin; Fojta, Miroslav; Šťastný, Jiří; Mergny, Jean-Louis (2019-09-15). Hancock, John (ed.).

3126:"Telomere Repeat-Binding Factor 2 Binds Extensively to Extra-Telomeric G-quadruplexes and Regulates the Epigenetic Status of Several Gene Promoters" 3946:"Human Apurinic/Apyrimidinic Endonuclease (APE1) Is Acetylated at DNA Damage Sites in Chromatin, and Acetylation Modulates Its DNA Repair Activity" 2116:

Miyoshi D, Karimata H, Sugimoto N (June 2006). "Hydration regulates thermodynamics of G-quadruplex formation under molecular crowding conditions".

5784:

Haeusler AR, Donnelly CJ, Periz G, Simko EA, Shaw PG, Kim MS, Maragakis NJ, Troncoso JC, Pandey A, Sattler R, Rothstein JD, Wang J (March 2014).

5735:"The disease-associated r(GGGGCC)n repeat from the C9orf72 gene forms tract length-dependent uni- and multimolecular RNA G-quadruplex structures" 2994:"Metastases Suppressor NM23-H2 Interaction With G-quadruplex DNA Within c-MYC Promoter Nuclease Hypersensitive Element Induces c-MYC Expression" 916:. FMRP acts as a negative regulator of translation, and its binding stabilizes G-quadruplex structures in mRNA transcripts, inhibiting ribosome 3500: 806:

can detect G-quadruplexes based on size exclusion and specific interaction of G-quadruplex and protein nanocavity. The novel approach combines

662:

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

350:-wide surveys based on a quadruplex folding rule have been performed, which have identified 376,000 Putative Quadruplex Sequences (PQS) in the 1231:

Sen D, Gilbert W (July 1988). "Formation of parallel four-stranded complexes by guanine-rich motifs in DNA and its implications for meiosis".

486:

shift from the original damage guanine, 8-oxo-Gua, and represents DNA damage that causes changes in the structure. This form allows for the

2917:"The DEXH protein product of the DHX36 gene is the major source of tetramolecular quadruplex G4-DNA resolving activity in HeLa cell lysates" 205:. In addition, the propensity of g-quadruplex formation during transcription in RNA sequences with the potential to form mutually exclusive 3699:"Stimulation of human 8-oxoguanine-DNA glycosylase by AP-endonuclease: potential coordination of the initial steps in base excision repair" 2659:"An intramolecular G-quadruplex structure with mixed parallel/antiparallel G-strands formed in the human BCL-2 promoter region in solution" 977: 81:, or tetramolecular. Depending on the direction of the strands or parts of a strand that form the tetrads, structures may be described as 6576:

Campbell NH, Patel M, Tofa AB, Ghosh R, Parkinson GN, Neidle S (March 2009). "Selectivity in ligand recognition of G-quadruplex loops".

5419:

Bošković F, Zhu J, Chen K, Keyser UF (November 2019). "Monitoring G-Quadruplex Formation with DNA Carriers and Solid-State Nanopores".

3075:"Epigenetic Suppression of Human Telomerase ( hTERT) Is Mediated by the Metastasis Suppressor NME2 in a G-quadruplex-dependent Fashion" 909:

within the nucleus, and separation of nucleolin by the mutated RNA transcripts impairs nucleolar function and ribosomal RNA synthesis.

893:

repeats in DNA have the ability to form mixed parallel-antiparallel G-quadruplex structures as well. These RNA transcripts containing G

7098: 1494:"QuadBase: Genome-Wide Database of G4 DNA--occurrence and Conservation in Human, Chimpanzee, Mouse and Rat Promoters and 146 Microbes" 4905:"Intramolecularly folded G-quadruplex and i-motif structures in the proximal promoter of the vascular endothelial growth factor gene" 2858:"The Werner syndrome protein is distinguished from the Bloom syndrome protein by its capacity to tightly bind diverse DNA structures" 928:, and other neurological disorders. Specifically, Fragile X Syndrome is caused by an increase from 50 to over 200 CGG repeats within 457:(OGG1), APE1 and G-quadruplex play a huge role in its repair. These enzymes participate in BER to repair certain DNA lesions such as 3041:

Borman S (November 2009). "Promoter Quadruplexes Folded DNA structures in gene-activation sites may be useful cancer drug targets".

1639:

Borman S (November 2009). "Promoter quadruplexes folded DNA structures in gene-activation sites may be useful cancer drug targets".

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and bind them leading to the regulation of gene expression. Decoys have been successfully demonstrated to inhibit oncogenic KRAS in

2018:"G-Quadruplexes Involving Both Strands of Genomic DNA Are Highly Abundant and Colocalize with Functional Sites in the Human Genome" 1017:"G-quadruplex DNA sequences are evolutionarily conserved and associated with distinct genomic features in Saccharomyces cerevisiae" 924:

and controlling the timing of the transcript's expression. Mutations of this gene can cause the development of Fragile X Syndrome,

633:

this pathway suggested the formation of a G-quadruplex in the promoter region and an applicable target for therapeutic treatments.

5678:"C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes" 2243:"G-quadruplex formation at the 3' end of telomere DNA inhibits its extension by telomerase, polymerase and unwinding by helicase" 6973:"Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription" 4723:"Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription" 2551:"Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription" 7230:

Quadfinder: Tool for Prediction and Analysis of G Quadruplex Motifs in DNA/RNA Sequences from Maiti's group, IGIB, Delhi, India

6697:

Vilar R (2018). "Chapter 12. Nucleic Acid Quadruplexes and Metallo-Drugs". In Sigel A, Sigel H, Freisinger E, Sigel RK (eds.).

6444:"Allele-selective inhibition of mutant huntingtin expression with antisense oligonucleotides targeting the expanded CAG repeat" 4341:

Sharma S, Mukherjee AK, Roy SS, Bagri S, Lier S, Verma M, Sengupta A, Kumar M, Nesse G, Pandey DP, Chowdhury S (January 2020).

7210: 7108: 6393:

Carroll JB, Warby SC, Southwell AL, Doty CN, Greenlee S, Skotte N, Hung G, Bennett CF, Freier SM, Hayden MR (December 2011).

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repeats. The transcribed RNA of these repeats have been shown to form stable G-quadruplexes, with evidence showing that the G

831:(FTD). The second mechanism is through mutations that affect the expression of G-quadruplex binding proteins, as seen in the 4431:"Transcription Regulation of CDKN1A (p21/CIP1/WAF1) by TRF2 Is Epigenetically Controlled Through the REST Repressor Complex" 2153:"Molecular crowding creates an essential environment for the formation of stable G-quadruplexes in long double-stranded DNA" 3124:

Mukherjee AK, Sharma S, Bagri S, Kutum R, Kumar P, Hussain A, Singh P, Saha D, Kar A, Dash D, Chowdhury S (November 2019).

7195: 3995:"Regulatory role of human AP-endonuclease (APE1/Ref-1) in YB-1-mediated activation of the multidrug resistance gene MDR1" 389:

strand helps to maintain an open conformation of the coding DNA strand and enhance an expression of the respective gene.

6277:

Wheeler TM, Leger AJ, Pandey SK, MacLeod AR, Nakamori M, Cheng SH, Wentworth BM, Bennett CF, Thornton CA (August 2012).

4524:"Formation of pseudosymmetrical G-quadruplex and i-motif structures in the proximal promoter region of the RET oncogene" 4199: 2292:"In vitro generated antibodies specific for telomeric guanine-quadruplex DNA react with Stylonychia lemnae macronuclei" 1175:

Sundquist WI, Klug A (December 1989). "Telomeric DNA dimerizes by formation of guanine tetrads between hairpin loops".

333: 4342: 605:

regulation reported to be mediated through interaction of hTERT promoter G-quadruplex with the telomeric factor TRF2.

7172:– a website to discuss publications and other information of interest to those working in the field of G-quadruplexes 6714: 5242: 5573:

BL, Boeve BF, Uitti RJ, Boylan KB, Wszolek ZK, Graff-Radford NR, Dickson DW, Ross OA, Rademakers R (December 2012).

7213:- a web server to predict G-quadruplex forming motifs and other non-B DNA forming motifs from users' DNA sequences. 814:

for label-free detection of G-quadruplexes, for their mapping on dsDNA, and for monitoring G-quadruplex formation.

598: 31: 5135: 1969:"Computational detection and analysis of sequences with duplex-derived interstrand G-quadruplex forming potential" 6170:"Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS and frontotemporal degeneration" 5511: 2709:

Fernando H, Reszka AP, Huppert J, Ladame S, Rankin S, Venkitaraman AR, Neidle S, Balasubramanian S (June 2006).

7241:

pqsfinder: an exhaustive and imperfection-tolerant search tool for potential quadruplex-forming sequences in R.

7175: 7024:

Rawal P, Kummarasetti VB, Ravindran J, Kumar N, Halder K, Sharma R, Mukerji M, Das SK, Chowdhury S (May 2006).

4141: 2807:

Rawal P, Kummarasetti VB, Ravindran J, Kumar N, Halder K, Sharma R, Mukerji M, Das SK, Chowdhury S (May 2006).

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determination. The formation of these quadruplexes in telomeres has been shown to decrease the activity of the

940:

modifications of FMR1 that prevent the transcription of the gene, leading to pathological low levels of FMRP.

601:. Interaction of c-Myc promoter G-quadruplex with NM23H2 was shown to regulate c-Myc in cancer cells in 2009 992: 824: 5362:"Single-molecule investigation of G-quadruplex folds of the human telomere sequence in a protein nanocavity" 3073:

Saha D, Singh A, Hussain T, Srivastava V, Sengupta S, Kar A, Dhapola P, Ummanni R, Chowdhury S (July 2017).

1289:

Rawal P, Kummarasetti VB, Ravindran R, Kumar N, Halder K, Sharma R, Mukerji M, Das SK, Chowdhury S (2006).

7181: 2992:

Thakur RK, Kumar P, Halder K, Verma A, Kar A, Parent JL, Basundra R, Kumar A, Chowdhury S (January 2009).

2915:

Vaughn JP, Creacy SD, Routh ED, Joyner-Butt C, Jenkins GS, Pauli S, Nagamine Y, Akman SA (November 2005).

917: 7224:

QGRS Mapper: a web-based application for predicting G-quadruplexes in nucleotide sequences and NCBI genes

5933:"Translational regulation of the human achaete-scute homologue-1 by fragile X mental retardation protein" 4343:"Human Telomerase Expression is under Direct Transcriptional Control of the Telomere-binding-factor TRF2" 1345:

Borman S (May 28, 2007). "Ascent of quadruplexes nucleic acid structures become promising drug targets".

86: 4666:"A G-quadruplex-binding compound showing anti-tumour activity in an in vivo model for pancreatic cancer" 3529:"Endogenous oxidized DNA bases and APE1 regulate the formation of G-quadruplex structures in the genome" 475: 5529:

Ratnavalli E, Brayne C, Dawson K, Hodges JR (June 2002). "The prevalence of frontotemporal dementia".

3283:

Chen MC, Tippana R, Demeshkina NA, Murat P, Balasubramanian S, Myong S, Ferré-D'Amaré AR (June 2018).

2400:

single-stranded DNA self-condenses into compact beaded filaments stabilized by G-quadruplex formation"

5031: 4044:"Role of acetylated human AP-endonuclease (APE1/Ref-1) in regulation of the parathyroid hormone gene" 2711:"A conserved quadruplex motif located in a transcription activation site of the human c-kit oncogene" 478:(8-oxo-dG), is a known major product of DNA oxidation. Its concentration is used as a measurement of 6752: 6230:"Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion" 4239: 4091:

Yamamori T, DeRicco J, Naqvi A, Hoffman TA, Mattagajasingh I, Kasuno K, et al. (January 2010).

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hypersensitive region critical for gene activity. Other genes shown to form G-quadruplexes in their

7026:"Genome-wide prediction of G4 DNA as regulatory motifs: role in Escherichia coli global regulation" 3746:

Burrows CJ, Muller JG (May 1998). "Oxidative Nucleobase Modifications Leading to Strand Scission".

2809:"Genome-wide prediction of G4 DNA as regulatory motifs: role in Escherichia coli global regulation" 1768:

Müller, Sebastian; Kumari, Sunita; Rodriguez, Raphaël; Balasubramanian, Shankar (10 October 2010).

1408:

Han H, Hurley LH (April 2000). "G-quadruplex DNA: a potential target for anti-cancer drug design".

1291:"Genome-wide Prediction of G4 DNA as Regulatory Motifs: Role in Escherichia Coli Global Regulation" 382: 3389:

Hänsel-Hertsch R, Beraldi D, Lensing SV, Marsico G, Zyner K, Parry A, et al. (October 2016).

2451:"G-Quadruplex in Gene Encoding Large Subunit of Plant RNA Polymerase II: A Billion-Year-Old Story" 369:. There are several possible models for how quadruplexes could influence gene activity, either by 5088: 1127: 828: 272:, which is responsible for maintaining length of telomeres and is involved in around 85% of all 5931:

Fähling M, Mrowka R, Steege A, Kirschner KM, Benko E, Förstera B, et al. (February 2009).

5676:

Fratta P, Mizielinska S, Nicoll AJ, Zloh M, Fisher EM, Parkinson G, Isaacs AM (December 2012).

5472:"G-quadruplexes: Emerging roles in neurodegenerative diseases and the non-coding transcriptome" 3527:

Roychoudhury S, Pramanik S, Harris HL, Tarpley M, Sarkar A, Spagnol G, et al. (May 2020).

538: 534: 491: 454: 406: 6070:"C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia: gain or loss of function?" 5843:"Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function" 1076:"A G-quadruplex DNA-affinity Approach for Purification of Enzymaticacvly Active G4 Resolvase1" 7259: 4781: 440:, was utilized to map both; damage in AP sites, and the enzyme responsible for its repair, 209:

or G-quadruplex structures depends heavily on the position of the hairpin-forming sequence.

7114: 6984: 6347: 6290: 6181: 5797: 5689: 5428: 5373: 4961: 4734: 4677: 4442: 3993:

Chattopadhyay R, Das S, Maiti AK, Boldogh I, Xie J, Hazra TK, et al. (December 2008).

3540: 3296: 3239: 2869: 2562: 2449:

Volná A, Bartas M, Karlický V, Nezval J, Kundrátová K, Pečinka P, et al. (July 2021).

2303: 2029: 1781: 1679: 1240: 1184: 1028: 973: 702:

TMPyP4, a cationic porphyrin, is a more well known G4 binding ligand that helps to repress

543: 487: 450: 74: 70: 5972: 3944:

Roychoudhury S, Nath S, Song H, Hegde ML, Bellot LJ, Mantha AK, et al. (March 2017).

8: 5590: 3610: 913: 610: 414: 198: 105:

structures with a high association of guanines, which was later identified in eukaryotic

82: 66: 39: 6988: 6611:

Ohnmacht SA, Neidle S (June 2014). "Small-molecule quadruplex-targeted drug discovery".

6351: 6294: 6185: 6120:"RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention" 5801: 5693: 5432: 5377: 4965: 4881: 4738: 4681: 4446: 3544: 3300: 3243: 2873: 2566: 2307: 2033: 1828:"Small-molecule–induced DNA damage identifies alternative DNA structures in human genes" 1785: 1683: 1244: 1188: 1032: 7050: 7025: 6954: 6929: 6911: 6886: 6868: 6843: 6825: 6800: 6740: 6728: 6674: 6647: 6553: 6528: 6468: 6443: 6419: 6394: 6370: 6335: 6311: 6278: 6254: 6229: 6204: 6169: 6144: 6119: 6094: 6069: 6015: 5872: 5818: 5785: 5761: 5734: 5710: 5677: 5653: 5628: 5599: 5574: 5554: 5452: 5396: 5361: 5342: 5253: 5116: 5064: 4985: 4929: 4904: 4845: 4820: 4698: 4665: 4646: 4597: 4572: 4548: 4523: 4463: 4430: 4405: 4380: 4361: 4279: 4254: 4227: 4210: 4117: 4092: 4019: 3994: 3970: 3945: 3918: 3893: 3866: 3841: 3814: 3789: 3671: 3646: 3619: 3594: 3563: 3528: 3494: 3482: 3418: 3366: 3341: 3317: 3284: 3260: 3227: 3203: 3176: 3152: 3125: 3101: 3074: 3018: 2993: 2892: 2857: 2833: 2808: 2784: 2759: 2735: 2710: 2683: 2658: 2634: 2609: 2477: 2450: 2426: 2393: 2374: 2267: 2242: 2177: 2152: 2052: 2017: 1993: 1968: 1944: 1919: 1900: 1852: 1827: 1802: 1769: 1750: 1616: 1591: 1567: 1542: 1518: 1493: 1469: 1444: 1315: 1290: 1264: 1208: 1100: 1075: 1051: 1016: 836: 811: 378: 304: 194: 7007: 6972: 5859: 5842: 5575:"Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype" 5329: 5312: 5202: 5177: 4782:"Structural basis for telomeric G-quadruplex targeting by naphthalene diimide ligands" 4780:

Collie GW, Promontorio R, Hampel SM, Micco M, Neidle S, Parkinson GN (February 2012).

4757: 4722: 4184:

Sequence, stability, and structure of G-quadruplexes and their interactions with drugs

4068: 4043: 3390: 2585: 2550: 2526: 2501: 1702: 1667: 1421: 238:

repeats in a variety of organisms have been shown to form these quadruplex structures

57:, which sits in a central channel between each pair of tetrads. They can be formed of 7139: 7104: 7085: 7055: 7012: 6959: 6916: 6873: 6830: 6787: 6720: 6710: 6679: 6628: 6593: 6558: 6509: 6473: 6424: 6375: 6316: 6259: 6209: 6149: 6099: 6050: 6007: 6003: 5954: 5913: 5864: 5823: 5766: 5715: 5658: 5604: 5546: 5493: 5456: 5444: 5401: 5334: 5293: 5258: 5238: 5207: 5158: 5108: 5069: 5051: 5012: 4977: 4934: 4885: 4850: 4801: 4762: 4703: 4638: 4602: 4553: 4504: 4468: 4410: 4365: 4323: 4284: 4270: 4215: 4195: 4164: 4122: 4073: 4024: 3975: 3923: 3871: 3819: 3763: 3728: 3723: 3698: 3676: 3624: 3568: 3486: 3474: 3466: 3456: 3410: 3371: 3322: 3265: 3208: 3157: 3106: 3023: 2938: 2897: 2838: 2789: 2740: 2688: 2639: 2590: 2531: 2482: 2431: 2366: 2331: 2326: 2291: 2272: 2223: 2182: 2133: 2098: 2057: 1998: 1949: 1892: 1857: 1807: 1742: 1738: 1707: 1621: 1572: 1523: 1474: 1425: 1390: 1320: 1256: 1200: 1154: 1144: 1105: 1056: 960: 677:

have been shown to bind intercalatively with G-quadruplexes, as well as the molecule

262: 140: 6732: 6019: 5558: 5120: 5047: 4650: 3422: 1904: 1754: 584:

regions of DNA, G-quadruplex structures have been identified in various human proto-

385:

of the gene, and hence de-activating it. In another model, quadruplex formed at the

7131: 7077: 7045: 7037: 7002: 6992: 6949: 6941: 6906: 6898: 6863: 6855: 6820: 6812: 6779: 6702: 6669: 6659: 6620: 6585: 6548: 6540: 6501: 6463: 6455: 6414: 6406: 6365: 6355: 6306: 6298: 6249: 6241: 6199: 6189: 6139: 6131: 6089: 6081: 6042: 5999: 5944: 5903: 5892:"Phosphorylation influences the translation state of FMRP-associated polyribosomes" 5876: 5854: 5813: 5805: 5756: 5746: 5705: 5697: 5648: 5640: 5594: 5586: 5538: 5483: 5436: 5391: 5381: 5346: 5324: 5285: 5248: 5230: 5197: 5189: 5150: 5100: 5089:"G4RNA screener web server: User focused interface for RNA G-quadruplex prediction" 5059: 5043: 4989: 4969: 4924: 4916: 4877: 4840: 4832: 4793: 4752: 4742: 4693: 4685: 4630: 4592: 4584: 4543: 4535: 4496: 4458: 4450: 4400: 4392: 4353: 4315: 4274: 4266: 4205: 4187: 4156: 4112: 4104: 4063: 4055: 4014: 4006: 3965: 3957: 3913: 3905: 3861: 3853: 3809: 3801: 3755: 3718: 3710: 3666: 3658: 3614: 3606: 3558: 3548: 3448: 3402: 3361: 3353: 3312: 3304: 3255: 3247: 3198: 3188: 3147: 3137: 3096: 3086: 3050: 3013: 3005: 2969: 2928: 2887: 2877: 2828: 2820: 2779: 2771: 2730: 2722: 2678: 2670: 2657:

Dai J, Dexheimer TS, Chen D, Carver M, Ambrus A, Jones RA, Yang D (February 2006).

2629: 2621: 2580: 2570: 2521: 2513: 2472: 2462: 2421: 2411: 2378: 2358: 2321: 2311: 2262: 2254: 2213: 2172: 2164: 2125: 2088: 2047: 2037: 1988: 1980: 1939: 1931: 1884: 1847: 1839: 1797: 1789: 1734: 1697: 1687: 1648: 1611: 1603: 1562: 1554: 1543:"QuadBase2: Web Server for Multiplexed Guanine Quadruplex Mining and Visualization" 1513: 1505: 1464: 1456: 1417: 1382: 1354: 1310: 1302: 1268: 1248: 1212: 1192: 1136: 1095: 1087: 1046: 1036: 854: 711: 517: 516:

alterations, or the modulation of gene expression. Upon insertion of 8-oxo-dG into

479: 23:

Structure of a G-quadruplex. Left: a G-tetrad. Right: an intramolecular G4 complex.

6801:"In vivo veritas: using yeast to probe the biological functions of G-quadruplexes" 5488: 5471: 5154: 2200:

Endoh T, Rode AB, Takahashi S, Kataoka Y, Kuwahara M, Sugimoto N (February 2016).

1074:

Routh ED, Creacy SD, Beerbower PE, Akman SA, Vaughn JP, Smaldino PJ (March 2017).

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Smith SS (2010). "Evolutionary expansion of structurally complex DNA sequences".

4191: 4160: 3595:"Base excision DNA repair levels in mitochondrial lysates of Alzheimer's disease" 3193: 2882: 2290:

Schaffitzel C, Berger I, Postberg J, Hanes J, Lipps HJ, Plückthun A (July 2001).

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Simonsson T (April 2001). "G-quadruplex DNA structures--variations on a theme".

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