00987nas a2200265 4500008004100000022001400041245013600055210006900191260007600260300001400336490000700350653001400357653001900371653002000390653001500410653000800425100001800433700003100451700002400482700002100506700002500527700002300552700001800575856012800593 2012 eng d a1433-785100aTuberculosis drug streptomycin as a potential cancer therapeutic: inhibition of miR-21 function by directly targeting its precursor0 aTuberculosis drug streptomycin as a potential cancer therapeutic aCOMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USAbWILEY-BLACKWELLcDEC a1019-10230 v5110aApoptosis10adrug discovery10aGene expression10ainhibitors10aRNA1 aBose, Debojit1 aJayaraj, Gopal, Gunanathan1 aSuryawanshi, Hemant1 aAgarwala, Prachi1 aPore, Subrata, Kumar1 aBanerjee, Rajkumar1 aMaiti, Souvik uhttps://library.ncl.res.in/content/tuberculosis-drug-streptomycin-potential-cancer-therapeutic-inhibition-mir-21-function-001862nas a2200169 4500008004100000022001400041245007400055210006900129260007100198300001400269490000800283520123900291100002501530700002101555700001801576856009801594 2013 eng d a1520-610600aEffect of loops and G-quartets on the stability of RNA G-quadruplexes0 aEffect of loops and Gquartets on the stability of RNA Gquadruple a1155 16TH ST, NW, WASHINGTON, DC 20036 USAbAMER CHEMICAL SOCcJUN a6896-69050 v1173 a

The loop length, loop composition, salt concentration, and number of G-quartets are major determinants of G-quadruplex stability. We examined the effect of each of these factors on the thermal stability and folding topology of a library of RNA quadruplexes. The thermal stability of G2 and G3 RNA quadruplexes was investigated upon varying the loop length (from 1-1-1 to 15-15-15) and salt concentration (from sequence 1 to 100 mM KCl), while the effect of loop composition was explored using 18 naturally occurring potential RNA quadruplexes predicted in untranslated regions (UTRs). We found loop length and quadruplex stability to be inversely related for G2 RNA quadruplexes and G3 RNA quadruplexes with shorter loops. However, melting temperature saturates for G3 RNA quadruplexes with longer loops. RNA G-quadruplexes with longer loops (G3 15-15-15) displayed T-m values significantly higher than the physiological temperature. This study thus highlights the need to modify the consensus motif presently used by quadruplex prediction tools. An increase in the loop size from 7 bases to IS bases in the consensus motif will add to its predictive value for the discovery of potential RNA quadruplexes across transcriptomes.

1 aPandey, Satyaprakash1 aAgarwala, Prachi1 aMaiti, Souvik uhttps://library.ncl.res.in/content/effect-loops-and-g-quartets-stability-rna-g-quadruplexes-002321nas a2200181 4500008004100000022001400041245010600055210006900161260007100230300001400301490000700315520160500322100002101927700002501948700001701973700001801990856013102008 2013 eng d a0006-296000aG-quadruplex augments translation in the 5 ` untranslated region of transforming growth factor beta 20 aGquadruplex augments translation in the 5 untranslated region of a1155 16TH ST, NW, WASHINGTON, DC 20036 USAbAMER CHEMICAL SOCcMAR a1528-15380 v523 a

Transforming growth factor beta 2 (TGF beta 2) is a versatile cytokine with a prominent role in cell migration, invasion, cellular development, and immunomodulation. TGF beta 2 promotes the malignancy of tumors by inducing epithelial-mesenchymal transition, angiogenesis, and immunosuppression. As it is well-documented that nucleic acid secondary structure can regulate gene expression, we assessed whether any secondary motif regulates its expression at the post-transcriptional level. Bioinformatics analysis predicts an existence of a 23-nucleotide putative G-quadruplex sequence (PG4) in the 5' untranslated region (UTR) of TGF beta 2 mRNA. The ability of this stretch of sequence to form a highly stable, intramolecular parallel quadruplex was demonstrated using ultraviolet and circular dichroism spectroscopy. Footprinting studies further validated its existence in the presence of a neighboring nucleotide sequence. Following structural characterization, we evaluated the biological relevance of this secondary motif using a dual luciferase assay. Although PG4 inhibits the expression of the reporter gene, its presence in the context of the entire 5' UTR sequence interestingly enhances gene expression. Mutation or removal of the G-quadruplex sequence from the 5' UTR of the gene diminished the level of expression of this gene at the translational level. Thus, here we highlight an activating role of the G-quadruplex in modulating gene expression of TGF beta 2 at the translational level and its potential to be used as a target for the development of therapeutics against cancer.

1 aAgarwala, Prachi1 aPandey, Satyaprakash1 aMapa, Koyeli1 aMaiti, Souvik uhttps://library.ncl.res.in/content/g-quadruplex-augments-translation-5-untranslated-region-transforming-growth-factor-beta-2-001528nas a2200229 4500008004100000022001400041245005000055210004900105260007700154300001400231490000700245520082100252653001901073653001401092653002201106653001301128653001301141100002101154700002501175700001801200856008001218 2013 eng d a1439-422700aG-Quadruplexes as tools for synthetic biology0 aGQuadruplexes as tools for synthetic biology aBOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANYbWILEY-V C H VERLAG GMBHcNOV a2077-20810 v143 a

With the potential to engineer biological systems, synthetic biology is an emerging field that combines various disciplines of sciences. It encompasses combinations of DNA, RNA and protein modules for constructing desired systems and the rewiring of existing signalling networks. Despite recent advances, this field still lags behind in the artificial reconstruction of cellular processes, and thus demands new modules and switches to create genetic circuits. The widely characterised noncanonical nucleic acid secondary structures, G-quadruplexes are promising candidates to be used as biological modules in synthetic biology. Structural plasticity and functional versatility are significant G-quadruplex traits for its integration into a biological system and for diverse applications in synthetic circuits.

10aG-quadruplexes10aribozymes10asynthetic biology10atopology10azipcodes1 aAgarwala, Prachi1 aPandey, Satyaprakash1 aMaiti, Souvik uhttps://library.ncl.res.in/content/g-quadruplexes-tools-synthetic-biology-002537nas a2200241 4500008004100000022001400041245005100055210005000106260007300156300001400229490000900243520183400252653001002086653001202096653000902108653001002117653001702127653000802144100002102152700002502173700001802198856007902216 2014 eng d a0304-416500aRole of G-quadruplex located at 5 end of mRNAs0 aRole of Gquadruplex located at 5 end of mRNAs aPO BOX 211, 1000 AE AMSTERDAM, NETHERLANDSbELSEVIER SCIENCE BVcDEC a3503-35100 v18403 a

Background: Secondary structures in 5' UTR of mRNAs play a critical role in regulating protein synthesis. Though studies have indicated the role of secondary structure G-quadruplex in translational regulation, position-specific effect of G-quadruplex in naturally occurring mRNAs is still not understood. As a pre-initiation complex recognises 5' cap of the mRNA and scans along the untranslated region (UTR) before initiating translation, the presence of G-quadruplex in 5' region may have a significant contribution in regulating translation. Here, we investigate the role of G-quadruplex located at the 5' end of an mRNA. Methods: Biophysical characterisation of putative G-quadruplexes was performed using UV and CD spectroscopy. Functional implication of G-quadruplex in the context of their location was assessed in cellulo using gRT-PCR and dual luciferase assay system. Results: PG4 sequences in 5' UTR of AICT interacting protein (AKTIP), cathepsin B (CTSB) and forkhead box E3 (FOXE3) mRNAs form G-quadruplex whereas it is unable to form G-quadruplex in apolipoprotein A-I binding protein (APOA1BP). Our results demonstrated diverse roles of G-quadruplex located at 5' end of mRNAs. Though G-quadruplex in AKTIP and CTSB mRNA act as inhibitory modules, it activates translation in FOXE3 mRNA. Conclusions: Our works suggests that G-quadruplex present at the 5' terminal of an mRNA behaves differently in a different gene context. It can activate or inhibit gene expression. General significance: This study demonstrated that it is difficult to predict the role of G-quadruplex on the basis of its position in 5' UTR. The neighbouring nucleotide sequence, the intracellular milieu and the interacting partners might render diverse functions to this secondary structure. (C) 2014 Elsevier B.V. All rights reserved.

10aAKTIP10aAPOA1BP10aCTSB10aFOXE310aG-quadruplex10aUTR1 aAgarwala, Prachi1 aPandey, Satyaprakash1 aMaiti, Souvik uhttps://library.ncl.res.in/content/role-g-quadruplex-located-5-end-mrnas-001999nas a2200181 4500008004100000022001400041245008200055210006900137260007100206300001400277490000800291520132600299100002101625700001901646700002501665700001801690856010901708 2015 eng d a1520-610600aHuman telomeric RNA G-quadruplex response to point mutation in the G-quartets0 aHuman telomeric RNA Gquadruplex response to point mutation in th a1155 16TH ST, NW, WASHINGTON, DC 20036 USAbAMER CHEMICAL SOCcAPR a4617-46270 v1193 a

Many putative G-quadruplex forming sequences have been predicted to exist in the human genome and transcriptome. As these sequences are subject to point mutations or SNPs (single nucleotide polymorphisms) during the course of evolution, we attempt to understand impact of these mutations in context of RNA G-quadruplex formation using human telomeric RNA (TERRA) as a model sequence. Our studies suggest that G-quadruplex stability is sensitive to substitution of the guanines comprising G-quartets. While central G-quartet plays a crucial role in maintaining the DNA G-quadruplex stability as evident in literature, there is equal importance of three G-quartets in the stability of RNA quadruplex structure. The work here highlights the alterations in the G-quartet are detrimental to the integrity of overall RNA G-quadruplex structure. Furthermore, TmPyP4 molecules are shown to exhibit similar binding behavior toward telomeric RNA G-quadruplex harboring base substitutions employing CD titrations and isothermal titration calorimetry; well indicating that mutation does not influence TmPyP4 recognition ability as it affects the stability of RNA G-quadruplex. Thus, our study implicates that mutation in G-quartets causes destabilization of RNA G-quadruplex without affecting its trans factor binding ability.

1 aAgarwala, Prachi1 aKumar, Santosh1 aPandey, Satyaprakash1 aMaiti, Souvik uhttps://library.ncl.res.in/content/human-telomeric-rna-g-quadruplex-response-point-mutation-g-quartets-002126nas a2200193 4500008004100000022001400041245009800055210006900153260007100222300001400293490000700307520137200314100002501686700002101711700003101732700002301763700001801786856012801804 2015 eng d a0006-296000aRNA stem-loop to G-quadruplex equilibrium controls mature MicroRNA production inside the cell0 aRNA stemloop to Gquadruplex equilibrium controls mature MicroRNA a1155 16TH ST, NW, WASHINGTON, DC 20036 USAbAMER CHEMICAL SOCcDEC a7067-70780 v543 a

The biological role of the existence of overlapping structures in RNA is possible yet remains very unexplored. G-Rich tracts of RNA form G-quadruplexes, while GC-rich sequences prefer stem-loop structures. The equilibrium between alternate structures within RNA may occur and influence its functionality. We tested the equilibrium between G-quadruplex and stem-loop structure in RNA and its effect on biological processes using pre-miRNA as a model system. Dicer enzyme recognizes canonical stem-loop structures in pre-miRNA to produce mature miRNAs. Deviation from stem-loop leads to deregulated mature miRNA levels, providing readout of the existence of an alternate structure per se G-quadruplex-mediated structural interference in miRNA maturation. In vitro analysis using beacon and Dicer cleavage assays indicated that mature miRNA levels depend on relative amounts of K+: and Mg2+ ions, suggesting an ion-dependent structural shift. Further in cellulo studies with and without TmPyP4 (RNA G-quadruplex destabilizer) demonstrated that miRNA biogenesis is modulated by G-quadruplex to stem-loop equilibrium in a subset of pre-miRNAs. Our combined analysis thus provides evidence of the formation of noncanonical G-quaciruplexes in competition with canonical stem-loop structure inside the cell and its effect on miRNA maturation in a comprehensive manner.

1 aPandey, Satyaprakash1 aAgarwala, Prachi1 aJayaraj, Gopal, Gunanathan1 aGargallo, Raimundo1 aMaiti, Souvik uhttps://library.ncl.res.in/content/rna-stem-loop-g-quadruplex-equilibrium-controls-mature-microrna-production-inside-cell-001466nas a2200169 4500008004100000022001400041245002900055210002800084260011000112300001400222490000700236520092600243100002101169700002501190700001801215856006301233 2015 eng d a1477-052000aTale of RNA G-quadruplex0 aTale of RNA Gquadruplex aTHOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLANDbROYAL SOC CHEMISTRYcAPR a5570-55850 v133 a

G-quadruplexes are non-canonical secondary structures found in guanine rich regions of DNA and RNA. Reports have indicated the wide occurrence of RNA G-quadruplexes across the transcriptome in various regions of mRNAs and non-coding RNAs. RNA G-quadruplexes have been implicated in playing an important role in translational regulation, mRNA processing events and maintenance of chromosomal end integrity. In this review, we summarize the structural and functional aspects of RNA G-quadruplexes with emphasis on recent progress to understand the protein/trans factors binding these motifs. With the revelation of the importance of these secondary structures as regulatory modules in biology, we have also evaluated the various advancements towards targeting these structures and the challenges associated with them. Apart from this, numerous potential applications of this secondary motif have also been discussed.

1 aAgarwala, Prachi1 aPandey, Satyaprakash1 aMaiti, Souvik uhttps://library.ncl.res.in/content/tale-rna-g-quadruplex-001896nas a2200145 4500008004100000245007200041210006900113260002000182300001200202520136900214100002501583700002101608700001801629856010301647 2017 eng d00aTargeting RNA G-Quadruplexes for potential therapeutic applications0 aTargeting RNA GQuadruplexes for potential therapeutic applicatio bSpringer Verlag a177-2063 a

RNA G-quadruplexes are non-canonical structures formed in G-rich regions of transcriptome. Considerable research points towards the potential role for these dynamic structures in various genes involved in multiple pathways. The ability of these structures to influence important biological processes has been demonstrated in few selected important genes and more recently in a global manner across the transcriptome. RNA G-quadruplexes are implicated in fundamental processes such as translational regulation, alternative splicing, mRNA transport and telomere homeostasis to name a few. The involvement of these structures in key biological processes makes them attractive targets for therapeutic interventions. Here we discuss the structural features of RNA G-quadruplex that make it more monomorphic to develop ligands unlike the polymorphic DNA G-quadruplexes. Furthermore, the role of RNA G-quadruplexes in important genes involved in diseases and disorders such as neurodegeneration, cancer and viral infections has been highlighted. A summary of ligands and their established roles in targeting RNA G-quadruplex structures has been discussed in context of important processes. Moreover, we highlight the need to develop ligands that are highly specific in targeting RNA G-quadruplexes, a new target to restore homeostasis in dysregulated conditions.

1 aPandey, Satyaprakash1 aAgarwala, Prachi1 aMaiti, Souvik uhttps://library.ncl.res.in/content/targeting-rna-g-quadruplexes-potential-therapeutic-applications