Structural analysis reveals the formation and role of RNA G-quadruplex structures in human mature microRNAs

Chan, K.L; Peng, Boya; Umar, Mubarak Ishaq; Chan, Ckk; Sahakyan, Aleksandr B.; Le, Minh Vuong; Kwok, Chun Kit

doi:10.1039/c8cc04635b

Cited by 46 publications

(50 citation statements)

References 35 publications

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“…A similar result was observed when we used hTELO dG4, the DNA version of TERRA rG4. Moreover, we tested l ‐Ap3‐7 with six other d ‐RNA constructs that were previously reported to fold into parallel rG4s, namely hTERC , NRAS , miRNA149, miRNA197, miRNA432, and miRNA765, and found no observable binding. Due to its high specificity, we wondered how TERRA rG4 was involved in the binding.…”

Section: Figurementioning

confidence: 95%

Specific Binding of a d‐RNA G‐Quadruplex Structure with an l‐RNA Aptamer

Chan

Kwok

2020

Angewandte Chemie

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G‐quadruplex (G4) structures are of general importance in chemistry and biology, such as in biosensing, gene regulation, and cancers. Although a large repertoire of G4‐binding tools has been developed, no aptamer has been developed to interact with G4. Moreover, the G4 selectivity of current toolkits is very limited. Herein, we report the first l‐RNA aptamer that targets a d‐RNA G‐quadruplex (rG4). Using TERRA rG4 as an example, our results reveal that this l‐RNA aptamer, Ap3‐7, folds into a unique secondary structure, exhibits high G4 selectivity and effectively interferes with TERRA‐rG4–RHAU53 binding. Our approach and findings open a new door in further developing G4‐specific tools for diverse applications.

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Section: Figurementioning

confidence: 95%

Specific Binding of a d‐RNA G‐Quadruplex Structure with an l‐RNA Aptamer

Chan

Kwok

2020

Angewandte Chemie

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“…[89][90][91][92][93] The stability of two-quartet RNA GQs would implicate that shorter RNA molecules such as microRNAs may form GQs under physiological conditions and modulate the cellular functions. 94 In addition, these less stable GQs could have interesting dynamic properties, as they can quickly fold and unfold, and sensitively respond to the changes in cellular conditions. Various two-quartet GQs could be transiently formed during folding of larger GQs.…”

Section: Potential Roles Of Two-quartet Gqsmentioning

confidence: 99%

Stability of Two-quartet G-quadruplexes and Their Dimers in Atomistic Simulations

Islam

Stadlbauer

Vorlı́čková

et al. 2019

Preprint

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G-quadruplexes (GQ) are four-stranded non-canonical DNA and RNA architectures that can be formed by guanine-rich sequences. The stability of GQs increases with the number of G-quartets and three G-quartets generally form stable GQs. However, stability of two-quartet GQs is an open issue. To understand the intrinsic stability of two-quartet GQ stems, we have carried out a expression. 5 Therefore, there is considerable interest in studying and modulating the formation of GQs as a means for controlling gene expression and other cellular processes. 6 GQs are formed by stacking of planar guanine quartets, creating the G-stem. The O6 atoms of all the guanines face to form a central electron-rich channel within the GQ where cations bind and coordinate with the O6 atoms. This coordination is essential for GQ stability. 7 Bases not involved in G-stem belong to bulges, flanking nucleotides or participate in the loops linking the G-strands of the GQs. 3The GQs can be monomolecular, bimolecular or tetramolecular depending on the number of DNA or RNA molecules that form the GQ. 8,9 The topologies of GQs are highly variable as the G-strand orientation can be parallel or antiparallel and based on that GQs can fold into parallel, antiparallel or hybrid topology. 10,11 The guanines in the DNA GQs can adopt syn or anti orientation. 10,12,13 In the RNA GQs, the 2 -hydroxyl group in ribose allows for more interactions with the bases, cations and water molecules thereby increasing their stability, as common in RNA molecules. [14][15][16][17][18][19] It also restricts the orientation of the guanine bases favouring the anti-orientation. 14 Therefore, the majority of the RNA GQs have been observed in the parallel-stranded topology with all bases in the anti-orientation. [15][16][17][18] The loops further add to the diversity as the GQs can have propeller, lateral or diagonal loops. 8,[20][21][22][23][24][25][26][27] The parallel-stranded GQ have propeller (double-chain reversal) loops as they are necessary to orient the following and preceding G-strands in a parallel arrangement. 8 The antiparallel and hybrid GQs can have various combinations of the three loop types. [20][21][22][23][24][25][26][27] The overall GQ topology dictates the loop combination as well as the allowable syn-anti patterns of the guanines. Na + ions tend to coordinate within the plane while K + ions coordinate between the planes of the G-quartets. 28,29 The cation-quadruplex interactions can induce kinetic and equilibrium differences between the different topologies. 28,30,31 Stability of GQs is affected by the number of G-quartets in the stem. 14,[32][33][34] It is commonly accepted that increasing the number of G-quartets usually stabilizes the GQ structure. 12,14,34,35 In DNA, stable GQ structures generally involve three quartets or more, although stable antiparallel two-quartet GQs with loop alignments or stacked triads have also been observed. 21, 36 27 In such GQs, additional interactions formed by the loops or triads above and/or below the G-stems contribut...

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“…For each of the three candidates we performed multiple assays to provide additional support for the formation of G4s at the RNA level (Kwok & Merrick 2017), (Chan et al 2018), (Chan et al 2019). First, we performed circular dichroism spectroscopy and UV-melting measurements of the G4-containing RNA oligonucleotides, in the presence of lithium ions (non-G4 stabilising) or potassium ions (G4 stabilizing), to examine the formation potential and stability of RNA G4s.…”

Section: Dynamic Splicing Responses To Stimuli Are Associated With Prmentioning

confidence: 99%

“…ThT ligand enhanced fluorescence. This assay was performed similar to our previous work (Chan et al 2018). Briefly, sample solutions containing 1 µM RNA were prepared in 150 mM LiCl/KCl, 10 mM LiCac buffer (pH 7.0) and 1 µM ThT ligand.…”

mentioning

confidence: 99%

Alternative splicing modulation by G-quadruplexes

Soares

Parada

Wong

et al. 2019

Preprint

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Alternative splicing is central to metazoan gene regulation but the regulatory mechanisms involved are only partially understood. Here, we show that G-quadruplex (G4) motifs are enriched ~3-fold both upstream and downstream of splice junctions. Analysis of in vitro G4-seq data corroborates their formation potential. G4s display the highest enrichment at weaker splice sites, which are frequently involved in alternative splicing events. The importance of G4s in RNA as supposed to DNA is emphasized by a higher enrichment for the non-template strand. To explore if G4s are involved in dynamic alternative splicing responses, we analyzed RNA-seq data from mouse and human neuronal cells treated with potassium chloride. We find that G4s are enriched at exons which were skipped following potassium ion treatment. We validate the formation of stable G4s for three candidate splice sites by circular dichroism spectroscopy, UV-melting and fluorescence measurements. Finally, we explore G4 motifs across eleven representative species, and we observe that strong enrichment at splice sites is restricted to mammals and birds.

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Structural analysis reveals the formation and role of RNA G-quadruplex structures in human mature microRNAs

Cited by 46 publications

References 35 publications

Specific Binding of a d‐RNA G‐Quadruplex Structure with an l‐RNA Aptamer

Specific Binding of a d‐RNA G‐Quadruplex Structure with an l‐RNA Aptamer

Stability of Two-quartet G-quadruplexes and Their Dimers in Atomistic Simulations

Alternative splicing modulation by G-quadruplexes

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