RNA G-Quadruplexes in Biology: Principles and Molecular Mechanisms

Fay, Marta M.; Lyons, Shawn M.; Ivanov, Pavel

doi:10.1016/j.jmb.2017.05.017

Cited by 330 publications

(313 citation statements)

References 174 publications

(203 reference statements)

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“…The formation of RG4 structures — if validated inside cells — would represent the most stable RNA structure that could block ribosome scanning. Beyond the helicase eIF4A and in contrast to the extensively studied DNA G-quadruplexes 62 , other physiological roles of RG4s in mRNAs have only fairly recently been explored (reviewed in REFS 63,64) and include roles in mRNA processing and translation regulation (reviewed in REFS 65,66). Most examples of RG4s in 5′ UTRs are linked to translation repression in cis 65,67,68 presumably by preventing the 43S pre-initiation complex from binding to mRNA or by slowing down scanning 69,70 (FIG.…”

Section: ′ Utr Structures In Ribosome Scanningmentioning

confidence: 99%

Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them

Leppek

Das

Barna

2017

Nat Rev Mol Cell Biol

617

645

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RNA molecules can fold into intricate shapes that can provide an additional layer of control of gene expression beyond that of their sequence. In this Review, we discuss the current mechanistic understanding of structures in 5′ untranslated regions (UTRs) of eukaryotic mRNAs and the emerging methodologies used to explore them. These structures may regulate cap-dependent translation initiation through helicase-mediated remodelling of RNA structures and higher-order RNA interactions, as well as cap-independent translation initiation through internal ribosome entry sites (IRESs), mRNA modifications and other specialized translation pathways. We discuss known 5′ UTR RNA structures and how new structure probing technologies coupled with prospective validation, particularly compensatory mutagenesis, are likely to identify classes of structured RNA elements that shape post-transcriptional control of gene expression and the development of multicellular organisms.

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Section: ′ Utr Structures In Ribosome Scanningmentioning

confidence: 99%

Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them

Leppek

Das

Barna

2017

Nat Rev Mol Cell Biol

617

645

View full text Add to dashboard Cite

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“…G-quadruplexes are formed when guanines are organized into planar quartets in which each base is connected to two other bases via Hoogsteen base pairing. Hydrogen bonds between each pair of guanines involve four donor/acceptor atoms, so G-quadruplexes have eight hydrogen bonds in total [112]. However, in some cases, very stable G-quadruplex aptamers have shown cross-binding to several different proteins.…”

Section: G-quadruplexes In Aptamer Structuresmentioning

confidence: 99%

Aptamers: Uptake mechanisms and intracellular applications

Yoon

Rossi

2018

Advanced Drug Delivery Reviews

115

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The structural flexibility and small size of aptamers enable precise recognition of cellular elements for imaging and therapeutic applications. The process by which aptamers are taken into cells depends on their targets but is typically clathrin-mediated endocytosis or macropinocytosis. After internalization, most aptamers are transported to endosomes, lysosomes, endoplasmic reticulum, Golgi apparatus, and occasionally mitochondria and autophagosomes. Intracellular aptamers, or "intramers," have versatile functions ranging from intracellular RNA imaging, gene regulation, and therapeutics to allosteric modulation, which we discuss in this review. Immune responses to therapeutic aptamers and the effects of G-quadruplex structure on aptamer function are also discussed.

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“…3C). 141 Each G-tetrad has four guanines arranged in a square planar arrangement and held together by Hoogsteen hydrogen bonding. Further stabilization of each G4-RNA is then achieved through the presence of a monovalent cation, most often potassium, which is localized in the center between each pair of tetrads.…”

Section: Rna G-quadruplexesmentioning

confidence: 99%

“…Further stabilization of each G4-RNA is then achieved through the presence of a monovalent cation, most often potassium, which is localized in the center between each pair of tetrads. 141 G-quadruplexes has been first described in DNA, 142 yet there are key structural differences between DNA and RNA G4s that may further the therapeutic targeting of G4-RNA. In general, RNA G4s have higher stability attributed to differences in hydration and increased intramolecular hydrogen bonding due to 2′ of ribose sugar.…”

Section: Rna G-quadruplexesmentioning

confidence: 99%

Unveiling the druggable RNA targets and small molecule therapeutics

Sztuba-Solińska

Chávez-Calvillo

Cline

2019

Bioorganic & Medicinal Chemistry

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Keywords:RNA structure and function RNA interactions Epitranscriptomics Small molecules RNA-based therapeutics RNA in disease Drug target A B S T R A C T The increasing appreciation for the crucial roles of RNAs in infectious and non-infectious human diseases makes them attractive therapeutic targets. Coding and non-coding RNAs frequently fold into complex conformations which, if effectively targeted, offer opportunities to therapeutically modulate numerous cellular processes, including those linked to undruggable protein targets. Despite the considerable skepticism as to whether RNAs can be targeted with small molecule therapeutics, overwhelming evidence suggests the challenges we are currently facing are not outside the realm of possibility. In this review, we highlight the most recent advances in molecular techniques that have sparked a revolution in understanding the RNA structure-to-function relationship. We bring attention to the application of these modern techniques to identify druggable RNA targets and to assess small molecule binding specificity. Finally, we discuss novel screening methodologies that support RNA drug discovery and present examples of therapeutically valuable RNA targets. RNA as a drug targetThe vast diversity of RNAs expanding beyond coding transcripts to several classes of ncRNAs that vary in length, biogenesis, polarity, and putative functions, increases the repertoire of druggable targets. 19,20 Here, specific RNA properties contribute to its attractive, yet challenging makeup as a target molecule. RNA can form complex three-dimensional structures through canonical Watson-Crick base pairing and complex tertiary interactions that are mediated by non-canonical bonds. Such structures can be as intricate and stable as those formed by proteins and can recognize small-molecule ligands, other nucleic acids, and/or proteins with high affinity and specificity. [21][22][23][24] At the same time, the highly dynamic conformation and repetitive character of its surface presents difficulties for drug design. 25,26 In addition, many putative small molecule-binding pockets in RNA are much more polar and solvent exposed than binding sites on proteins, complicating ligand design efforts. Compounding these issues, most target RNAs are expressed at low levels, with the exception of ribosomal (rRNA) and transfer (tRNA) RNAs, which constitute 80-90% and 10-15% of total cellular RNA, respectively. 27 Other abundant RNAs, such as messenger (mRNA), small nuclear (snRNA), and small nucleolar (snoRNA) are present at levels that are about 1-2 orders of magnitude lower than rRNA and tRNA. Certain small RNAs, such as micro (miRNA) and piwi (piRNAs) can be present at very high levels; however, this appears to be cell type dependent. One should keep in mind that if the RNA has catalytic activity or if it acts as a scaffold to regulate https://doi.

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RNA G-Quadruplexes in Biology: Principles and Molecular Mechanisms

Cited by 330 publications

References 174 publications

Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them

Functional 5′ UTR mRNA structures in eukaryotic translation regulation and how to find them

Aptamers: Uptake mechanisms and intracellular applications

Unveiling the druggable RNA targets and small molecule therapeutics

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