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Cold Spring Harbor Perspectives in... Dec 2018RNA molecules are folded into structures and complexes to perform a wide variety of functions. Determination of RNA structures and their interactions is a fundamental... (Review)
Review
RNA molecules are folded into structures and complexes to perform a wide variety of functions. Determination of RNA structures and their interactions is a fundamental problem in RNA biology. Most RNA molecules in living cells are large and dynamic, posing unique challenges to structure analysis. Here we review progress in RNA structure analysis, focusing on methods that use the "cross-link, proximally ligate, and sequence" principle for high-throughput detection of base-pairing interactions in living cells. Beginning with a comparison of commonly used methods in structure determination and a brief historical account of psoralen cross-linking studies, we highlight the important features of cross-linking methods and new biological insights into RNA structures and interactions from recent studies. Further improvement of these cross-linking methods and application to previously intractable problems will shed new light on the mechanisms of the "modern RNA world."
Topics: Base Pairing; Gene Expression Regulation; Nucleic Acid Conformation; RNA
PubMed: 30510063
DOI: 10.1101/cshperspect.a034926 -
The Journal of Physical Chemistry. B Nov 2020Double-stranded (ds)DNA formation and dissociation are of fundamental biological importance. The negative DNA charge influences the dsDNA stability. However, the base...
Double-stranded (ds)DNA formation and dissociation are of fundamental biological importance. The negative DNA charge influences the dsDNA stability. However, the base pairing and the stacking between neighboring bases are responsible for the sequence-dependent stability of dsDNA. The stability of a dsDNA molecule can be estimated from empirical nearest-neighbor models based on contributions assigned to base-pair steps along the DNA and additional parameters because of DNA termini. In efforts to separate contributions, it has been concluded that base stacking dominates dsDNA stability, whereas base pairing contributes negligibly. Using a different model for dsDNA formation, we reanalyze dsDNA stability contributions and conclude that base stacking contributes already at the level of separate ssDNAs but that pairing contributions drive the dsDNA formation. The theoretical model also predicts that stability contributions of base-pair steps that contain only guanine/cytosine, mixed steps, and steps with only adenine/thymine follow the order 6:5:4, respectively, as expected based on the formed hydrogen bonds. The model is fully consistent with the available stacking data and the nearest-neighbor dsDNA parameters. It allows assigning a narrowly distributed value for the effective free energy contribution per formed hydrogen bond during dsDNA formation of -0.72 kcal·mol based entirely on the experimental data.
Topics: Base Pairing; Cytosine; DNA; Hydrogen Bonding; Thermodynamics; Thymine
PubMed: 33156627
DOI: 10.1021/acs.jpcb.0c07670 -
Chemical Society Reviews Jun 2009The naturally occurring nucleic acid bases (nucleobases) adenine, thymine (uracil), guanine, and cytosine are widely appreciated for their ability to stabilize canonical... (Review)
Review
The naturally occurring nucleic acid bases (nucleobases) adenine, thymine (uracil), guanine, and cytosine are widely appreciated for their ability to stabilize canonical Watson-Crick base-pairing motifs, as well as a number of other well-characterized arrangements, such as Hoogsteen and wobble heterodimers, and a variety of homodimers. In this tutorial review, the use of these kinds of interactions to form synthetic polymeric and oligomeric ensembles is summarized. Particular emphasis will be placed on synthetic analogues of guanine that stabilize the formation of well-defined higher order aggregates, as well as de novo polymeric systems whose properties are modulated by the presence of nucleobase derivatives incorporated within or attached to the chain-defining backbone. In both cases, nucleobase-nucleobase interactions serve to underlie the chemistry, establish the structural morphology, and enable the development of bioinspired, environmentally responsive materials.
Topics: Base Pairing; Biomimetic Materials; Dimerization; Guanine; Polymers
PubMed: 19587956
DOI: 10.1039/b806484a -
FEMS Microbiology Reviews Sep 2010Bacteria use a range of RNA regulators collectively termed small RNAs (sRNAs) to help respond to changes in the environment. Many sRNAs regulate their target mRNAs... (Review)
Review
Bacteria use a range of RNA regulators collectively termed small RNAs (sRNAs) to help respond to changes in the environment. Many sRNAs regulate their target mRNAs through limited base-pairing interactions. Ongoing characterization of base-pairing sRNAs in bacteria has started to reveal how these sRNAs participate in global regulatory networks. These networks can be broken down into smaller regulatory circuits that have characteristic behaviors and functions. In this review, we describe the specific regulatory circuits that incorporate base-pairing sRNAs and the importance of each circuit in global regulation. Because most of these circuits were originally identified as network motifs in transcriptional networks, we also discuss why sRNAs may be used over protein transcription factors to help transduce environmental signals.
Topics: Bacteria; Base Pairing; Gene Expression Regulation, Bacterial; Gene Regulatory Networks; RNA, Bacterial; RNA, Small Untranslated; Transcription Factors
PubMed: 20662934
DOI: 10.1111/j.1574-6976.2010.00241.x -
Metal Ions in Life Sciences 2012Base-pairing in the naturally occurring DNA and RNA oligonucleotide duplexes is based on π-stacking, hydrogen bonding, and shape complementarity between the nucleobases... (Review)
Review
Base-pairing in the naturally occurring DNA and RNA oligonucleotide duplexes is based on π-stacking, hydrogen bonding, and shape complementarity between the nucleobases adenine, thymine, guanine, and cytosine as well as on the hydrophobic-hydrophilic balance in aqueous media. This complex system of multiple supramolecular interactions is the product of a long-term evolutionary process and thus highly optimized to serve its biological functions such as information storage and processing. After the successful implementation of automated DNA synthesis, chemists have begun to introduce artificial modifications inside the core of the DNA double helix in order to study various aspects of base pairing, generate new base pairs orthogonal to the natural ones, and equip the biopolymer with entirely new functions. The idea to replace the hydrogen bonding interactions with metal coordination between ligand-like nucleosides and suitable transition metal ions culminated in the development of a plethora of artificial base-pairing systems termed "metal base-pairs" which were shown to strongly enhance the DNA duplex stability. Furthermore, they show great potential for the use of DNA as a molecular wire in nanoscale electronic architectures. Although single electrons have proven to be transmitted by natural DNA over a distance of several base pairs, the high ohmic resistance of unmodified oligonucleotides was identified as a serious obstacle. By exchanging some or all of the Watson-Crick base pairs in DNA with metal complexes, this problem may be solved. In the future, these research efforts are supposed to lead to DNA-like materials with superior conductivity for nano-electronic applications. Other fields of potential application such as DNA-based supramolecular architecture and catalysis may be strongly influenced by these developments as well. This text is meant to illustrate the basic concepts of metal-base pairing and give an outline over recent developments in this field.
Topics: Base Pairing; Coordination Complexes; DNA; Metals; Molecular Structure; Nucleic Acid Conformation
PubMed: 22210343
DOI: 10.1007/978-94-007-2172-2_10 -
Inorganic Chemistry Oct 2023The synthesis and base pairing properties of platinum complexes based on uridine and deoxyuridine nucleosides and preliminary studies of their antiproliferative activity...
The synthesis and base pairing properties of platinum complexes based on uridine and deoxyuridine nucleosides and preliminary studies of their antiproliferative activity are described. Platinum(II) uridine and deoxyuridine complexes were synthesized by C-I oxidative addition to Pt(0)(PPh). First, the synthesis was performed with protected nucleosides to generate complexes and , which were deprotected under basic conditions, affording complexes and in good yields. The synthesis with the unprotected nucleosides was also performed and provided complexes and effectively. Base pairing interactions were measured for complex , either for self-base pairing or for the Watson-Crick base pair. Complex undergoes self-base pairing in CDCl, and this aggregation was found not to be dependent on metalation. Contrastingly, for the Watson-Crick base pair with adenine, base pairing was also observed, but metalation was found to affect hydrogen bonding considerably. Complexes and and the corresponding ligand precursors were evaluated for their antiproliferative activity against human glioblastoma cell line U-251. The compounds showed IC values of 3.30 () and 1.84 () μM but are also toxic for nontumorous cell lines.
Topics: Humans; Base Pairing; Platinum; Nucleosides; Uridine; Uracil; Deoxyuridine; Hydrogen Bonding
PubMed: 37768109
DOI: 10.1021/acs.inorgchem.3c02071 -
Nature Structural & Molecular Biology Jun 2017
Topics: Base Pairing; Base Sequence; Nucleic Acid Conformation; RNA
PubMed: 28586329
DOI: 10.1038/nsmb.3425 -
Nucleic Acids Research Apr 2022Unnatural base pairs (UBPs) which exhibit a selectivity against pairing with canonical nucleobases provide a powerful tool for the development of nucleic acid-based...
Unnatural base pairs (UBPs) which exhibit a selectivity against pairing with canonical nucleobases provide a powerful tool for the development of nucleic acid-based technologies. As an alternative strategy to the conventional UBP designs, which involve utility of different recognition modes at the Watson-Crick interface, we now report that the exclusive base pairing can be achieved through the spatial separation of recognition units. The design concept was demonstrated with the alkynylated purine (NPu, OPu) and pyridazine (NPz, OPz) nucleosides endowed with nucleobase-like 2-aminopyrimidine or 2-pyridone ('pseudo-nucleobases') on their major groove side. These alkynylated purines and pyridazines exhibited exclusive and stable pairing properties by the formation of complementary hydrogen bonds between the pseudo-nucleobases in the DNA major groove as revealed by comprehensive Tm measurements, 2D-NMR analyses, and MD simulations. Moreover, the alkynylated purine-pyridazine pairs enabled dramatic stabilization of the DNA duplex upon consecutive incorporation while maintaining a high sequence-specificity. The present study showcases the separation of the recognition interface as a promising strategy for developing new types of UBPs.
Topics: Base Pairing; DNA; Hydrogen Bonding; Nucleic Acid Conformation; Nucleic Acids; Nucleosides
PubMed: 35234916
DOI: 10.1093/nar/gkac140 -
Nucleic Acids Research Nov 2023There are >170 naturally occurring RNA chemical modifications, with both known and unknown biological functions. Analytical methods for detecting chemical modifications...
There are >170 naturally occurring RNA chemical modifications, with both known and unknown biological functions. Analytical methods for detecting chemical modifications and for analyzing their effects are relatively limited and have had difficulty keeping pace with the demand for RNA chemical biology and biochemistry research. Some modifications can affect the ability of RNA to hybridize with its complementary sequence or change the selectivity of base pairing. Here, we investigate the use of affinity-based DNA nanoswitches to resolve energetic differences in hybridization. We found that a single m3C modification can sufficiently destabilize hybridization to abolish a detection signal, while an s4U modification can selectively hybridize with G over A. These results establish proof of concept for using DNA nanoswitches to detect certain RNA modifications and analyzing their effects in base pairing stability and specificity.
Topics: Base Pairing; Base Sequence; DNA; Nucleic Acid Hybridization; RNA
PubMed: 37811879
DOI: 10.1093/nar/gkad802 -
Nucleic Acids Research Aug 2020RNA-small molecule binding is a key regulatory mechanism which can stabilize 3D structures and activate molecular functions. The discovery of RNA-targeting compounds is...
RNA-small molecule binding is a key regulatory mechanism which can stabilize 3D structures and activate molecular functions. The discovery of RNA-targeting compounds is thus a current topic of interest for novel therapies. Our work is a first attempt at bringing the scalability and generalization abilities of machine learning methods to the problem of RNA drug discovery, as well as a step towards understanding the interactions which drive binding specificity. Our tool, RNAmigos, builds and encodes a network representation of RNA structures to predict likely ligands for novel binding sites. We subject ligand predictions to virtual screening and show that we are able to place the true ligand in the 71st-73rd percentile in two decoy libraries, showing a significant improvement over several baselines, and a state of the art method. Furthermore, we observe that augmenting structural networks with non-canonical base pairing data is the only representation able to uncover a significant signal, suggesting that such interactions are a necessary source of binding specificity. We also find that pre-training with an auxiliary graph representation learning task significantly boosts performance of ligand prediction. This finding can serve as a general principle for RNA structure-function prediction when data is scarce. RNAmigos shows that RNA binding data contains structural patterns with potential for drug discovery, and provides methodological insights for possible applications to other structure-function learning tasks. The source code, data and a Web server are freely available at http://rnamigos.cs.mcgill.ca.
Topics: Base Pairing; Binding Sites; Ligands; Nucleic Acid Conformation; RNA; Software
PubMed: 32652015
DOI: 10.1093/nar/gkaa583