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1.
J Am Chem Soc ; 146(12): 8005-8015, 2024 03 27.
Artículo en Inglés | MEDLINE | ID: mdl-38498910

RESUMEN

Intracellular chemical microenvironments, including ion concentrations and molecular crowding, play pivotal roles in cell behaviors, such as proliferation, differentiation, and cell death via regulation of gene expression. However, there is no method for quantitative analysis of intracellular environments due to their complexity. Here, we have developed a system for highlighting the environment inside of the cell (SHELL). SHELL is a pseudocellular system, wherein small molecules are removed from the cell and a crowded intracellular environment is maintained. SHELL offers two prominent advantages: (1) It allows for precise quantitative biochemical analysis of a specific factor, and (2) it enables the study of any cell, thereby facilitating the study of target molecule effects in various cellular environments. Here, we used SHELL to study G-quadruplex formation, an event that implicated cancer. We show that G-quadruplexes are more stable in SHELL compared with in vitro conditions. Although malignant transformation perturbs cellular K+ concentrations, environments in SHELL act as buffers against G-quadruplex destabilization at lower K+ concentrations. Notably, the buffering effect was most pronounced in SHELL derived from nonaggressive cancer cells. Stable G-quadruplexes form due to the binding of the G-quadruplex with K+ in different cancer cells. Furthermore, the observed pattern of G-quadruplex-induced transcriptional inhibition in SHELL is consistent with that in living cells at different cancer stages. Our results indicate that ion binding to G-quadruplexes regulates gene expression during pathogenesis.


Asunto(s)
G-Cuádruplex , Muerte Celular , Diferenciación Celular
2.
ACS Omega ; 9(5): 5675-5682, 2024 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-38343917

RESUMEN

G-quadruplexes in disease-related genes are associated with various biological processes and regulate disease progression. Although methods involving ligands and other techniques are available to stabilize G-quadruplexes, approaches for destabilizing G-quadruplexes remain limited. Here, we evaluated whether G-quadruplexes can be destabilized using choline dihydrogen phosphate (choline dhp), a highly biocompatible hydrated ionic liquid. Circular dichroism spectral measurements at increasing temperatures revealed that choline dhp destabilized G-quadruplexes more effectively than did KCl-containing solutions. Thermodynamic analysis indicated that destabilization occurred via an entropic contribution, suggesting that choline ions did not coordinate with the G-quartets, because of their large radii. Subsequently, plasmid DNAs containing G-quadruplexes were constructed, and transcription reactions were performed in nuclear extracts from living cells. G-quadruplexes repressed transcription, whereas the addition of choline dhp increased transcription. Although ionic liquids often inactivate biomolecules, choline dhp can be used to culture various cells. Furthermore, the transcription of template DNA containing the G-quadruplex was greatly enhanced in living MDA-MD-231 cells (aggressive human breast cancer cells) cultured with choline dhp. Our results show that choline dhp destabilizes G-quadruplexes in cells, indicating that choline dhp can regulate gene expression. Thus, choline dhp may be useful for regulating target disease-related genes.

3.
J Am Chem Soc ; 145(43): 23503-23518, 2023 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-37873979

RESUMEN

In cells, the formation of RNA/DNA hybrid duplexes regulates gene expression and modification. The environment inside cellular organelles is heterogeneously crowded with high concentrations of biomolecules that affect the structure and stability of RNA/DNA hybrid duplexes. However, the detailed environmental effects remain unclear. Therefore, the mechanistic details of the effect of such molecular crowding were investigated at the molecular level by using thermodynamic and nuclear magnetic resonance analyses, revealing structure-dependent destabilization of the duplexes under crowded conditions. The transition from B- to A-like hybrid duplexes due to a change in conformation of the DNA strand guided by purine-pyrimidine asymmetry significantly increased the hydration number, which resulted in greater destabilization by the addition of cosolutes. By quantifying the individual contributions of environmental factors and the bulk structure of the duplex, we developed a set of parameters that predict the stability of hybrid duplexes with conformational dissimilarities under diverse crowding conditions. A comparison of the effects of environmental conditions in living cells and in vitro crowded solutions on hybrid duplex formation using the Förster resonance energy transfer technique established the applicability of our parameters to living cells. Moreover, our derived parameters can be used to estimate the efficiency of transcriptional inhibition, genome editing, and silencing techniques in cells. This supports the usefulness of our parameters for the visualization of cellular mechanisms of gene expression and the development of nucleic acid-based therapeutics targeting different cells.


Asunto(s)
Oligonucleótidos , ARN , Oligonucleótidos/química , ARN/química , Secuencia de Bases , Conformación de Ácido Nucleico , ADN/química , Termodinámica
4.
Nucleic Acids Res ; 51(9): 4101-4111, 2023 05 22.
Artículo en Inglés | MEDLINE | ID: mdl-36718808

RESUMEN

RNA performs various spatiotemporal functions in living cells. As the solution environments significantly affect the stability of RNA duplexes, a stability prediction of the RNA duplexes in diverse crowded conditions is required to understand and modulate gene expression in heterogeneously crowded intracellular conditions. Herein, we determined the nearest-neighbor (NN) parameters for RNA duplex formation when subjected to crowding conditions with an ionic concentration relevant to that found in cells. Determination of the individual contributions of excluded volume effect and water activity to each of the NN parameters in crowded environments enabled prediction of the thermodynamic parameters and their melting temperatures for plenty of tested RNA duplex formation in vitro and in cell with significant accuracy. The parameters reported herein will help predicting RNA duplex stability in different crowded environments, which will lead to an improved understanding of the stability-function relationship for RNAs in various cellular organelles with different molecular environments.


Asunto(s)
Conformación de Ácido Nucleico , Estabilidad del ARN , ARN , ARN/química , ARN/genética , ARN/metabolismo , Temperatura , Termodinámica , Agua/química , Agua/metabolismo
5.
Sci Adv ; 8(47): eadc9785, 2022 11 25.
Artículo en Inglés | MEDLINE | ID: mdl-36417515

RESUMEN

Climate change negatively affects crop yield, which hinders efforts to reach agricultural sustainability and food security. Here, we show that a previously unidentified allele of the nitrate transporter gene OsNRT2.3 is required to maintain high yield and high nitrogen use efficiency under high temperatures. We demonstrate that this tolerance to high temperatures in rice accessions harboring the HTNE-2 (high temperature resistant and nitrogen efficient-2) alleles from enhanced translation of the OsNRT2.3b mRNA isoform and the decreased abundance of a unique small RNA (sNRT2.3-1) derived from the 5' untranslated region of OsNRT2.3. sNRT2.3-1 binds to the OsNRT2.3a mRNA in a temperature-dependent manner. Our findings reveal that allelic variation in the 5' untranslated region of OsNRT2.3 leads to an increase in OsNRT2.3b protein levels and higher yield during high-temperature stress. Our results also provide a breeding strategy to produce rice varieties with higher grain yield and lower N fertilizer input suitable for a sustainable agriculture that is resilient against climate change.


Asunto(s)
Proteínas de Transporte de Anión , Oryza , Proteínas de Transporte de Anión/genética , Proteínas de Transporte de Anión/metabolismo , Regulación de la Expresión Génica de las Plantas , Alelos , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Temperatura , Regiones no Traducidas 5' , Nitratos/metabolismo , Fitomejoramiento , Oryza/genética , Oryza/metabolismo , Nitrógeno/metabolismo
6.
Chem Commun (Camb) ; 58(93): 12931-12934, 2022 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-36321741

RESUMEN

We constructed a minimum liquid-liquid phase separation model system to form liquid droplets using only G-quadruplex-forming oligonucleotides and R- and G-rich oligopeptides. We found that the G-quadruplex structure is an essential component for RNA to form droplets with the peptide. Based on this model system and our findings, droplet redissolution via structure transition from a G-quadruplex to a duplex was achieved in a sequence-specific manner.


Asunto(s)
G-Cuádruplex , Dicroismo Circular , Oligonucleótidos/química , ARN
7.
Chem Commun (Camb) ; 58(89): 12459-12462, 2022 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-36263745

RESUMEN

Since DNA methylation alters the chromatin state and regulates gene expression, elucidating the regulatory mechanisms of DNA methylation in response to environmental changes in the cell is crucial and urgent in understanding and regulating DNA methylation. G-quadruplex (G4) regulates transcription, translation and replication. Although it has recently been suggested that G4 regulates methylation, the detailed regulatory mechanism remains unclear. Here, we systematically analysed the effect of G4 formation on DNA methylation using G4s with various stabilities and topologies. The methylation efficiency decreased as the stability of G4 increased. Moreover, the degree of methylation suppression can be also controlled by G4 topology. Furthermore, our results showed the possibility of regulating methylation by modulating G4 stability and topology.


Asunto(s)
Metilación de ADN , G-Cuádruplex
8.
Chem Commun (Camb) ; 58(1): 48-51, 2021 Dec 21.
Artículo en Inglés | MEDLINE | ID: mdl-34811561

RESUMEN

We identified cytosine-rich regions adjacent to guanine-rich regions in protease genes. A typical GC-rich sequence derived from the TMPRSS2 gene showed structural competition between a G-quadruplex and a hairpin loop, and this competition significantly affected transcription efficiency. These results suggest an impact of neighboring sequences on the gene expression of guanine-rich sequences.


Asunto(s)
Serina Endopeptidasas/genética , Exones , G-Cuádruplex , Secuencia Rica en GC , Humanos
9.
J Am Chem Soc ; 143(40): 16458-16469, 2021 10 13.
Artículo en Inglés | MEDLINE | ID: mdl-34554731

RESUMEN

Ligands that bind to and stabilize guanine-quadruplex (G4) structures to regulate DNA replication have therapeutic potential for cancer and neurodegenerative diseases. Because there are several G4 topologies, ligands that bind to their specific types may have the ability to preferentially regulate the replication of only certain genes. Here, we demonstrated that binding ligands stalled the replication of template DNA at G4, depending on different topologies. For example, naphthalene diimide derivatives bound to the G-quartet of G4 with an additional interaction between the ligand and the loop region of a hybrid G4 type from human telomeres, which efficiently repressed the replication of the G4. Thus, these inhibitory effects were not only stability-dependent but also topology-selective based on the manner in which G4 structures interacted with G4 ligands. Our original method, referred to as a quantitative study of topology-dependent replication (QSTR), was developed to evaluate correlations between replication rate and G4 stability. QSTR enabled the systematic categorization of ligands based on topology-dependent binding. It also demonstrated accuracy in determining quantitatively how G4 ligands control the intermediate state of replication and the kinetics of G4 unwinding. Hence, the QSTR index would facilitate the design of new drugs capable of controlling the topology-dependent regulation of gene expression.


Asunto(s)
G-Cuádruplex
11.
Nucleic Acids Res ; 49(14): 7839-7855, 2021 08 20.
Artículo en Inglés | MEDLINE | ID: mdl-34244785

RESUMEN

Cancer and neurodegenerative diseases are caused by genetic and environmental factors. Expression of tumour suppressor genes is suppressed by mutations or epigenetic silencing, whereas for neurodegenerative disease-related genes, nucleic acid-based effects may be presented through loss of protein function due to erroneous protein sequences or gain of toxic function from extended repeat transcripts or toxic peptide production. These diseases are triggered by damaged genes and proteins due to lifestyle and exposure to radiation. Recent studies have indicated that transient, non-canonical structural changes in nucleic acids in response to the environment can regulate the expression of disease-related genes. Non-canonical structures are involved in many cellular functions, such as regulation of gene expression through transcription and translation, epigenetic regulation of chromatin, and DNA recombination. Transcripts generated from repeat sequences of neurodegenerative disease-related genes form non-canonical structures that are involved in protein transport and toxic aggregate formation. Intracellular phase separation promotes transcription and protein assembly, which are controlled by the nucleic acid structure and can influence cancer and neurodegenerative disease progression. These findings may aid in elucidating the underlying disease mechanisms. Here, we review the influence of non-canonical nucleic acid structures in disease-related genes on disease onset and progression.


Asunto(s)
Neoplasias/genética , Enfermedades Neurodegenerativas/genética , Conformación de Ácido Nucleico , Ácidos Nucleicos/química , Secuencias Repetitivas de Ácidos Nucleicos/genética , Animales , Epigénesis Genética , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Neoplasias/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Ácidos Nucleicos/genética , Ácidos Nucleicos/metabolismo
12.
RSC Adv ; 11(59): 37205-37217, 2021 Nov 17.
Artículo en Inglés | MEDLINE | ID: mdl-35496393

RESUMEN

Patterns and levels of DNA modifications play important roles in senescence. Two major epigenetic modifications of DNA, 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC), target CpG sites. Importantly, CpG concentrated regions, known as CpG islands, contain GC-rich sequences, which have the potential to fold into non-canonical DNA structures such as i-motifs and G-quadruplexes. In this study, we investigated the effect of 5mC and 5hmC modifications on the transition between a duplex, and i-motif and G-quadruplexes. To examine the transition, we firstly investigated the stability and structure of the i-motif and G-quadruplexes, considering the molecular environment in senescent cells. Analyses of their stability showed that the modifications did not drastically affect the stability. However, noteworthily, the modification can weaken the (de)stabilisation effect on G-quadruplexes caused by cosolute(s) and cations. Circular dichroism analyses indicated that the surrounding environments, including the molecular crowding and the type of cations such as K+ and Na+, regulate the topology of G-quadruplexes, while neither 5mC nor 5hmC had a drastic effect. On the other hand, the modifications changed the transition between duplexes and quadruplexes. Unmodified DNA preferred to fold into quadruplexes, whereas DNA with 5mC and 5hmC preferred to fold into duplexes in the absence of PEG200; on the other hand, DNA with or without modifications tended to fold into i-motifs under crowded conditions. Furthermore, an investigation of quadruplexes forming sequences in CpG islands, which are hyper- or hypomethylated during senescence, followed by gene ontology enrichment analysis for each gene group classified by the presence of quadruplexes, showed a difference in function between genes with and without quadruplexes in the CpG region. These results indicate that it is important to consider the effects of patterns and levels of DNA modifications on the transition between canonical and non-canonical DNA structures to understand gene regulation by epigenetic modification during senescence.

13.
Nucleic Acids Res ; 48(21): 12042-12054, 2020 12 02.
Artículo en Inglés | MEDLINE | ID: mdl-32663294

RESUMEN

The stability of Watson-Crick paired RNA/DNA hybrids is important for designing optimal oligonucleotides for ASO (Antisense Oligonucleotide) and CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-Cas9 techniques. Previous nearest-neighbour (NN) parameters for predicting hybrid stability in a 1 M NaCl solution, however, may not be applicable for predicting stability at salt concentrations closer to physiological condition (e.g. ∼100 mM Na+ or K+ in the presence or absence of Mg2+). Herein, we report measured thermodynamic parameters of 38 RNA/DNA hybrids at 100 mM NaCl and derive new NN parameters to predict duplex stability. Predicted ΔG°37 and Tm values based on the established NN parameters agreed well with the measured values with 2.9% and 1.1°C deviations, respectively. The new results can also be used to make precise predictions for duplexes formed in 100 mM KCl or 100 mM NaCl in the presence of 1 mM Mg2+, which can mimic an intracellular and extracellular salt condition, respectively. Comparisons of the predicted thermodynamic parameters with published data using ASO and CRISPR-Cas9 may allow designing shorter oligonucleotides for these techniques that will diminish the probability of non-specific binding and also improve the efficiency of target gene regulation.


Asunto(s)
ADN/química , Oligonucleótidos Antisentido/química , Cloruro de Potasio/química , ARN/química , Cloruro de Sodio/química , Secuencia de Bases , Sistemas CRISPR-Cas , Cationes , ADN/metabolismo , Magnesio/química , Hibridación de Ácido Nucleico , Oligonucleótidos Antisentido/síntesis química , ARN/metabolismo , Análisis de Regresión , Sodio/química , Termodinámica
14.
Biochemistry ; 59(28): 2640-2649, 2020 07 21.
Artículo en Inglés | MEDLINE | ID: mdl-32578417

RESUMEN

G-Quadruplexes are noncanonical structures formed by guanine-rich regions of not only DNA but also RNA. RNA G-quadruplexes are widely present in the transcriptome as mRNAs and noncoding RNAs and take part in various essential functions in cells. Furthermore, stable RNA G-quadruplexes control the extent of biological functions, such as mRNA translation and antigen presentation. To understand and regulate the functions controlled by RNA G-quadruplexes in cellular environments, which are molecularly crowded, we would be required to investigate the stability of G-quadruplexes in molecular crowding. Here, we systematically investigated the thermodynamic stability of RNA G-quadruplexes with different numbers of G-quartets and lengths of loops. The molecular crowding conditions of polyethylene glycol with an average molecular weight of 200 (PEG200) were found to stabilize RNA G-quadruplexes with three and four G-quartets, while G-quadruplexes with two G-quartets did not exhibit any stabilization upon addition of PEG200. On the other hand, no difference in stabilization by PEG200 was observed among the G-quadruplexes with different loop lengths. Thermodynamic analysis of the RNA G-quadruplexes revealed more appropriate motifs for identifying G-quadruplex-forming sequences. The informatics analysis with new motifs demonstrated that the distributions of G-quadruplexes in human noncoding RNAs differed depending on the number of G-quartets. Therefore, RNA G-quadruplexes with different numbers of G-quartets may play different roles in response to environmental changes in cells.


Asunto(s)
G-Cuádruplex , ARN/química , Secuencia de Bases , Conformación de Ácido Nucleico , Polietilenglicoles/química , Estabilidad del ARN , Termodinámica
15.
Proc Natl Acad Sci U S A ; 117(25): 14194-14201, 2020 06 23.
Artículo en Inglés | MEDLINE | ID: mdl-32522884

RESUMEN

The intracellular environment is crowded and heterogeneous. Although the thermodynamic stability of nucleic acid duplexes is predictable in dilute solutions, methods of predicting such stability under specific intracellular conditions are not yet available. We recently showed that the nearest-neighbor model for self-complementary DNA is valid under molecular crowding condition of 40% polyethylene glycol with an average molecular weight of 200 (PEG 200) in 100 mM NaCl. Here, we determined nearest-neighbor parameters for DNA duplex formation under the same crowding condition to predict the thermodynamics of DNA duplexes in the intracellular environment. Preferential hydration of the nucleotides was found to be the key factor for nearest-neighbor parameters in the crowding condition. The determined parameters were shown to predict the thermodynamic parameters (∆H°, ∆S°, and ∆G°37) and melting temperatures (Tm) of the DNA duplexes in the crowding condition with significant accuracy. Moreover, we proposed a general method for predicting the stability of short DNA duplexes in different cosolutes based on the relationship between duplex stability and the water activity of the cosolute solution. The method described herein would be valuable for investigating biological processes that occur under specific intracellular crowded conditions and for the application of DNA-based biotechnologies in crowded environments.


Asunto(s)
ADN/química , Nucleótidos/química , Secuencia de Bases , ADN/genética , Estructura Molecular , Conformación de Ácido Nucleico , Polietilenglicoles , ARN/química , Estabilidad del ARN , Termodinámica
16.
Biochemistry ; 59(21): 1972-1980, 2020 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-32301603

RESUMEN

The regulatory mechanisms of the processes of RNA accumulation were examined from a chemical perspective in repeat-expansion disorders, which induce cytotoxicity and cause neurodegenerative diseases. We found that the accumulation, including production, gelation, and sedimentation, of RNA repeats transcribed from repeat expansions related to neurodegenerative diseases was greatly accelerated by G-quadruplex-forming RNA repeats, although no acceleration was induced by hairpin-forming RNA repeats. We also investigated the relationship between accumulation and physical solution properties, such as viscosity and water activity, and found that RNA accumulation was promoted through a decrease in the dielectric constant. Importantly, we found that the RNA accumulation required RNA G-quadruplexes and was promoted by changes in the dielectric property of the cell induced by an ion channel inhibitor. Our study is the first to show that the accumulation processes that induce toxicity in cells can be controlled via electrostatic interactions in the RNA G-quadruplex; thus, these can form the basis of guidelines for the chemical control of cell toxins.


Asunto(s)
G-Cuádruplex , Guanina/metabolismo , ARN/metabolismo , Secuencias Repetitivas de Ácidos Nucleicos , Guanina/química , Humanos , Microscopía Fluorescente , Imagen Óptica , ARN/química , Células Tumorales Cultivadas
17.
Molecules ; 25(3)2020 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-32041318

RESUMEN

Methods for stabilizing G-quadruplex formation is a promising therapeutic approach for cancer treatment and other biomedical applications because stable G-quadruplexes efficiently inhibit biological reactions. Oligo and polyethylene glycols are promising biocompatible compounds, and we have shown that linear oligoethylene glycols can stabilize G-quadruplexes. Here, we developed a new modified deoxythymine with dibranched or tribranched tetraethylene glycol (TEG) and incorporated these TEG-modified deoxythymines into a loop region that forms an antiparallel G-quadruplex. We analyzed the stability of the modified G-quadruplexes, and the results showed that the tribranched TEG destabilized G-quadruplexes through entropic contributions, likely through steric hindrance. Interestingly, the dibranched TEG modification increased G-quadruplex stability relative to the unmodified DNA structures due to favorable enthalpic contributions. Molecular dynamics calculations suggested that dibranched TEG interacts with the G-quadruplex through hydrogen bonding and CH-π interactions. Moreover, these branched TEG-modified deoxythymine protected the DNA oligonucleotides from degradation by various nucleases in human serum. By taking advantage of the unique interactions between DNA and branched TEG, advanced DNA materials can be developed that affect the regulation of DNA structure.


Asunto(s)
Polietilenglicoles/química , Timina/química , ADN/química , G-Cuádruplex , Humanos , Enlace de Hidrógeno , Simulación de Dinámica Molecular , Conformación de Ácido Nucleico , Oligonucleótidos/química
18.
Nucleic Acids Res ; 48(7): 3975-3986, 2020 04 17.
Artículo en Inglés | MEDLINE | ID: mdl-32095808

RESUMEN

Guanine-rich regions of the human genome can adopt non-canonical secondary structures. Their role in regulating gene expression has turned them into promising targets for therapeutic intervention. Ligands based on polyaromatic moieties are especially suitable for targeting G-quadruplexes utilizing their size complementarity to interact with the large exposed surface area of four guanine bases. A predictable way of (de)stabilizing specific G-quadruplex structures through efficient base stacking of polyaromatic functional groups could become a valuable tool in our therapeutic arsenal. We have investigated the effect of pyrene-modified uridine nucleotides incorporated at several positions of the thrombin binding aptamer (TBA) as a model system. Characterization using spectroscopic and biophysical methods provided important insights into modes of interaction between pyrene groups and the G-quadruplex core as well as (de)stabilization by enthalpic and entropic contributions. NMR data demonstrated that incorporation of pyrene group into G-rich oligonucleotide such as TBA may result in significant changes in 3D structure such as formation of novel dimeric topology. Site specific structural changes induced by stacking of the pyrene moiety on nearby nucleobases corelate with distinct thrombin binding affinities and increased resistance against nuclease degradation.


Asunto(s)
Aptámeros de Nucleótidos/química , G-Cuádruplex , Pirenos/química , Aptámeros de Nucleótidos/sangre , Aptámeros de Nucleótidos/metabolismo , Desoxirribonucleasas , Dimerización , Entropía , Humanos , Termodinámica , Trombina/metabolismo , Nucleótidos de Uracilo/química
19.
Artículo en Inglés | MEDLINE | ID: mdl-32081425

RESUMEN

Telomeric G-quadruplex topology has the ability to regulate telomerase activity, which counteracts the shortening of telomere with successive cell divisions, thereby causing genomic longevity. However, the detailed mechanism of G-quadruplexes topologies formed by telomeric sequences requires further investigation. In this study, we quantitatively investigated the effect of cosolutes, particularly the varying number of hydroxyl groups, on the structural transition between hybrid type and parallel G-quadruplexes formed by telomeric DNA sequences. Cosolutes with one or no hydroxyl groups in the vicinal position more efficiently induced the transition to parallel G-quadruplex from hybrid G-quadruplex than those with more hydroxyl groups. We also examined the effect of cosolute structures on the hydration of G-quadruplex formation; the results indicated that cosolutes with fewer hydroxyl groups lead to the release of greater amount of water during G-quadruplex formation. Molecular dynamics results showed that the parallel G-quadruplex was more dehydrated than the hybrid type G-quadruplex. Generally, a dehydrated structure is favored under crowding condition. Thus, depending on the surrounding cosolutes, the G-quadruplex topology can be controlled by the G-quadruplex hydration state.

20.
Chem Commun (Camb) ; 56(16): 2379-2390, 2020 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-32022004

RESUMEN

DNA forms not only the canonical duplex structure but also non-canonical structures. Most potential sequences that induce the formation of non-canonical structures are present in disease-related genes. Interestingly, biological reactions are inhibited or dysregulated by non-canonical structure formation in disease-related genes. To control biological reactions, methods for inducing the formation of non-canonical structures have been developed using small molecules and oligonucleotides. In this feature article, we review biological reactions such as replication, transcription, and reverse transcription controlled by non-canonical DNA structures formed by disease-related genes. Furthermore, we discuss recent studies aimed at developing methods for regulating these biological reactions using drugs targeting the DNA structure.


Asunto(s)
ADN/antagonistas & inhibidores , Preparaciones Farmacéuticas/química , Animales , ADN/química , ADN/metabolismo , Humanos , Conformación de Ácido Nucleico
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