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1.
Nucleic Acids Res ; 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31956910

RESUMO

We present a new coarse grained method for the simulation of duplex DNA. The algorithm uses a generalized multi-harmonic model that can represent any multi-normal distribution of helical parameters, thus avoiding caveats of current mesoscopic models for DNA simulation and representing a breakthrough in the field. The method has been parameterized from accurate parmbsc1 atomistic molecular dynamics simulations of all unique tetranucleotide sequences of DNA embedded in long duplexes and takes advantage of the correlation between helical states and backbone configurations to derive atomistic representations of DNA. The algorithm, which is implemented in a simple web interface and in a standalone package reproduces with high computational efficiency the structural landscape of long segments of DNA untreatable by atomistic molecular dynamics simulations.

2.
Biochemistry ; 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31815441

RESUMO

It is increasingly recognized that the structures and dynamics of G-quadruplex DNA molecules are dictated by their sequences and greatly affected by environmental factors. The core guanine tetrads (G-tetrads) coordinate cations and display a strong conformational rigidity compared with that of the connecting loops. Although long loops linking the G-tetrads are typically disfavored, when present, they provide a striking illustration of the dynamics of short, single-stranded DNA regions. In addition to their role in determining the stability of the G-quadruplex state, these loops are also interesting as potential drug targets. To characterize accurately the dynamics of this DNA state, we apply here the principles of structural ensemble determination developed in the past two decades for protein molecules to DNA molecules. We thus perform extensive molecular dynamics simulations restrained with nuclear magnetic resonance residual dipolar couplings to determine a structural ensemble of the human CEB25 minisatellite G-quadruplex, which contains a connecting loop of nine nucleotides. This structural ensemble displays a wide set of arrangements for the loop and a compact, well-defined G-quadruplex core. Our results show the importance of stacking interactions in the loop and strengthen the ability of the closing base pairs to confer a large thermodynamic stability to the G-quadruplex structure.

3.
Nucleic Acids Res ; 47(21): 11090-11102, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31624840

RESUMO

We present a multi-laboratory effort to describe the structural and dynamical properties of duplex B-DNA under physiological conditions. By processing a large amount of atomistic molecular dynamics simulations, we determine the sequence-dependent structural properties of DNA as expressed in the equilibrium distribution of its stochastic dynamics. Our analysis includes a study of first and second moments of the equilibrium distribution, which can be accurately captured by a harmonic model, but with nonlocal sequence-dependence. We characterize the sequence-dependent choreography of backbone and base movements modulating the non-Gaussian or anharmonic effects manifested in the higher moments of the dynamics of the duplex when sampling the equilibrium distribution. Contrary to prior assumptions, such anharmonic deformations are not rare in DNA and can play a significant role in determining DNA conformation within complexes. Polymorphisms in helical geometries are particularly prevalent for certain tetranucleotide sequence contexts and are always coupled to a complex network of coordinated changes in the backbone. The analysis of our simulations, which contain instances of all tetranucleotide sequences, allow us to extend Calladine-Dickerson rules used for decades to interpret the average geometry of DNA, leading to a set of rules with quantitative predictive power that encompass nonlocal sequence-dependence and anharmonic fluctuations.

4.
Sci Data ; 6(1): 169, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31506435

RESUMO

In the recent years, the improvement of software and hardware performance has made biomolecular simulations a mature tool for the study of biological processes. Simulation length and the size and complexity of the analyzed systems make simulations both complementary and compatible with other bioinformatics disciplines. However, the characteristics of the software packages used for simulation have prevented the adoption of the technologies accepted in other bioinformatics fields like automated deployment systems, workflow orchestration, or the use of software containers. We present here a comprehensive exercise to bring biomolecular simulations to the "bioinformatics way of working". The exercise has led to the development of the BioExcel Building Blocks (BioBB) library. BioBB's are built as Python wrappers to provide an interoperable architecture. BioBB's have been integrated in a chain of usual software management tools to generate data ontologies, documentation, installation packages, software containers and ways of integration with workflow managers, that make them usable in most computational environments.

5.
Nucleic Acids Res ; 47(18): 9511-9523, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31504766

RESUMO

We present Nucleosome Dynamics, a suite of programs integrated into a virtual research environment and created to define nucleosome architecture and dynamics from noisy experimental data. The package allows both the definition of nucleosome architectures and the detection of changes in nucleosomal organization due to changes in cellular conditions. Results are displayed in the context of genomic information thanks to different visualizers and browsers, allowing the user a holistic, multidimensional view of the genome/transcriptome. The package shows good performance for both locating equilibrium nucleosome architecture and nucleosome dynamics and provides abundant useful information in several test cases, where experimental data on nucleosome position (and for some cases expression level) have been collected for cells under different external conditions (cell cycle phase, yeast metabolic cycle progression, changes in nutrients or difference in MNase digestion level). Nucleosome Dynamics is a free software and is provided under several distribution models.


Assuntos
Genômica/métodos , Nucleossomos/genética , Software , Ciclo Celular/genética , Montagem e Desmontagem da Cromatina/genética , Genoma/genética , Nucleossomos/química , Nucleossomos/ultraestrutura , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Sítio de Iniciação de Transcrição , Transcriptoma/genética
6.
Acta Neuropathol ; 138(6): 1053-1074, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31428936

RESUMO

Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease.

7.
J Mol Biol ; 431(19): 3845-3859, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31325439

RESUMO

The rules governing sequence-specific DNA-protein recognition are under a long-standing debate regarding the prevalence of base versus shape readout mechanisms to explain sequence specificity and of the conformational selection versus induced fit binding paradigms to explain binding-related conformational changes in DNA. Using a combination of atomistic simulations on a subset of representative sequences and mesoscopic simulations at the protein-DNA interactome level, we demonstrate the prevalence of the shape readout model in determining sequence-specificity and of the conformational selection paradigm in defining the general mechanism for binding-related conformational changes in DNA. Our results suggest that the DNA uses a double mechanism to adapt its structure to the protein: it moves along the easiest deformation modes to approach the bioactive conformation, while final adjustments require localized rearrangements at the base-pair step and backbone level. Our study highlights the large impact of B-DNA dynamics in modulating DNA-protein binding.

8.
Bioinformatics ; 35(24): 5334-5336, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31286135

RESUMO

SUMMARY: veriNA3d is an R package for the analysis of nucleic acids structural data, with an emphasis in complex RNA structures. In addition to single-structure analyses, veriNA3d also implements functions to handle whole datasets of mmCIF/PDB structures that could be retrieved from public/local repositories. Our package aims to fill a gap in the data mining of nucleic acids structures to produce flexible and high throughput analysis of structural databases. AVAILABILITY AND IMPLEMENTATION: http://mmb.irbbarcelona.org/gitlab/dgallego/veriNA3d. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

9.
Nat Commun ; 10(1): 2034, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31048691

RESUMO

Polyglutamine (polyQ) tracts are regions of low sequence complexity frequently found in transcription factors. Tract length often correlates with transcriptional activity and expansion beyond specific thresholds in certain human proteins is the cause of polyQ disorders. To study the structural basis of the association between tract length, transcriptional activity and disease, we addressed how the conformation of the polyQ tract of the androgen receptor, associated with spinobulbar muscular atrophy (SBMA), depends on its length. Here we report that this sequence folds into a helical structure stabilized by unconventional hydrogen bonds between glutamine side chains and main chain carbonyl groups, and that its helicity directly correlates with tract length. These unusual hydrogen bonds are bifurcate with the conventional hydrogen bonds stabilizing α-helices. Our findings suggest a plausible rationale for the association between polyQ tract length and androgen receptor transcriptional activity and have implications for establishing the mechanistic basis of SBMA.


Assuntos
Atrofia Bulboespinal Ligada ao X/genética , Peptídeos/química , Conformação Proteica em alfa-Hélice/genética , Receptores Androgênicos/química , Fatores de Transcrição/química , Atrofia Bulboespinal Ligada ao X/patologia , Dicroísmo Circular , Glutamina/química , Humanos , Hidrogênio/química , Ligações de Hidrogênio , Espectroscopia de Ressonância Magnética , Simulação de Dinâmica Molecular , Mutação , Agregados Proteicos/genética , Receptores Androgênicos/genética , Fatores de Transcrição/genética
10.
Cell ; 177(4): 881-895.e17, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-31051106

RESUMO

Non-alcoholic fatty liver is the most common liver disease worldwide. Here, we show that the mitochondrial protein mitofusin 2 (Mfn2) protects against liver disease. Reduced Mfn2 expression was detected in liver biopsies from patients with non-alcoholic steatohepatitis (NASH). Moreover, reduced Mfn2 levels were detected in mouse models of steatosis or NASH, and its re-expression in a NASH mouse model ameliorated the disease. Liver-specific ablation of Mfn2 in mice provoked inflammation, triglyceride accumulation, fibrosis, and liver cancer. We demonstrate that Mfn2 binds phosphatidylserine (PS) and can specifically extract PS into membrane domains, favoring PS transfer to mitochondria and mitochondrial phosphatidylethanolamine (PE) synthesis. Consequently, hepatic Mfn2 deficiency reduces PS transfer and phospholipid synthesis, leading to endoplasmic reticulum (ER) stress and the development of a NASH-like phenotype and liver cancer. Ablation of Mfn2 in liver reveals that disruption of ER-mitochondrial PS transfer is a new mechanism involved in the development of liver disease.

11.
Nucleic Acids Res ; 47(12): 6519-6537, 2019 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-31114891

RESUMO

Human mitochondrial DNA (h-mtDNA) codes for 13 subunits of the oxidative phosphorylation pathway, the essential route that produces ATP. H-mtDNA transcription and replication depends on the transcription factor TFAM, which also maintains and compacts this genome. It is well-established that TFAM activates the mtDNA promoters LSP and HSP1 at the mtDNA control region where DNA regulatory elements cluster. Previous studies identified still uncharacterized, additional binding sites at the control region downstream from and slightly similar to LSP, namely sequences X and Y (Site-X and Site-Y) (Fisher et al., Cell 50, pp 247-258, 1987). Here, we explore TFAM binding at these two sites and compare them to LSP by multiple experimental and in silico methods. Our results show that TFAM binding is strongly modulated by the sequence-dependent properties of Site-X, Site-Y and LSP. The high binding versatility of Site-Y or the considerable stiffness of Site-X tune TFAM interactions. In addition, we show that increase in TFAM/DNA complex concentration induces multimerization, which at a very high concentration triggers disruption of preformed complexes. Therefore, our results suggest that mtDNA sequences induce non-uniform TFAM binding and, consequently, direct an uneven distribution of TFAM aggregation sites during the essential process of mtDNA compaction.

12.
Nucleic Acids Res ; 47(9): 4418-4430, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-30957854

RESUMO

We used extensive molecular dynamics simulations to study the structural and dynamic properties of the central d(TpA) step in the highly polymorphic d(CpTpApG) tetranucleotide. Contrary to the assumption of the dinucleotide-model and its nearest neighbours (tetranucleotide-model), the properties of the central d(TpA) step change quite significantly dependent on the next-to-nearest (hexanucleotide) sequence context and in a few cases are modulated by even remote neighbours (beyond next-to-nearest from the central TpA). Our results highlight the existence of previously undescribed dynamical mechanisms for the transmission of structural information into the DNA and demonstrate the existence of certain sequences with special physical properties that can impact on the global DNA structure and dynamics.


Assuntos
DNA/genética , Repetições de Dinucleotídeos/genética , Repetições de Microssatélites/genética , Análise de Sequência de DNA , Pareamento de Bases , Simulação de Dinâmica Molecular , Conformação de Ácido Nucleico
13.
Nat Chem ; 11(6): 533-542, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31011171

RESUMO

The physicochemical properties of nucleic acids are dominated by their highly charged phosphodiester backbone chemistry. This polyelectrolyte structure decouples information content (base sequence) from bulk properties, such as solubility, and has been proposed as a defining trait of all informational polymers. However, this conjecture has not been tested experimentally. Here, we describe the encoded synthesis of a genetic polymer with an uncharged backbone chemistry: alkyl phosphonate nucleic acids (phNAs) in which the canonical, negatively charged phosphodiester is replaced by an uncharged P-alkyl phosphonodiester backbone. Using synthetic chemistry and polymerase engineering, we describe the enzymatic, DNA-templated synthesis of P-methyl and P-ethyl phNAs, and the directed evolution of specific streptavidin-binding phNA aptamer ligands directly from random-sequence mixed P-methyl/P-ethyl phNA repertoires. Our results establish an example of the DNA-templated enzymatic synthesis and evolution of an uncharged genetic polymer and provide a foundational methodology for their exploration as a source of novel functional molecules.


Assuntos
DNA/química , Organofosfonatos/química , Aptâmeros de Nucleotídeos/química , DNA/síntese química , DNA/genética , DNA Polimerase Dirigida por DNA/química , DNA Polimerase Dirigida por DNA/genética , Evolução Molecular Direcionada/métodos , Mutação , Conformação de Ácido Nucleico , Organofosfonatos/síntese química , Engenharia de Proteínas/métodos , Estreptavidina/química , Thermococcaceae/enzimologia , Thermococcales/enzimologia
14.
Proc Natl Acad Sci U S A ; 116(20): 10009-10018, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31028138

RESUMO

Epidermal growth factor receptor (EGFR) signaling is initiated by a large ligand-favored conformational change of the extracellular domain (ECD) from a closed, self-inhibited tethered monomer, to an open untethered state, which exposes a loop required for strong dimerization and activation. In glioblastomas (GBMs), structurally heterogeneous missense and deletion mutations concentrate at the ECD for unclear reasons. We explore the conformational impact of GBM missense mutations, combining elastic network models (ENMs) with multiple molecular dynamics (MD) trajectories. Our simulations reveal that the main missense class, located at the I-II interface away from the self-inhibitory tether, can unexpectedly favor spontaneous untethering to a compact intermediate state, here validated by small-angle X-ray scattering (SAXS). Significantly, such intermediate is characterized by the rotation of a large ECD fragment (N-TR1), deleted in the most common GBM mutation, EGFRvIII, and that makes accessible a cryptic epitope characteristic of cancer cells. This observation suggested potential structural equivalence of missense and deletion ECD changes in GBMs. Corroborating this hypothesis, our FACS, in vitro, and in vivo data demonstrate that entirely different ECD variants all converge to remove N-TR1 steric hindrance from the 806-epitope, which we show is allosterically coupled to an intermediate kinase and hallmarks increased oncogenicity. Finally, the detected extraintracellular coupling allows for synergistic cotargeting of the intermediate with mAb806 and inhibitors, which is proved herein.

15.
Angew Chem Int Ed Engl ; 58(12): 3759-3763, 2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30681249

RESUMO

The energetics of intramolecular recognition processes are governed by the balance of pre-organization and flexibility, which is often difficult to measure and hard to predict. Using classical MD simulations, we predict and quantify the effective strength of intramolecular hydrogen bonds between donor and acceptor sites separated by a variable alkyl linker in several solvents and crowded solutions. The balance of entropic and enthalpic contributions poses a solvent-dependent limit to the occurrence of intramolecular H-bonding. Still, free energies show a constant offset among different solvents with, for example, a 13 kJ mol-1 difference between water and chloroform. Molecular crowding shows little effect on the thermodynamic equilibrium, but induces variations on the H-bond kinetics. The results are in quantitative agreement with experiments in chloroform and showcase a general strategy to investigate molecular interactions in different environments, extending the limits of current experiments towards the prospective prediction of H-bond interactions in a variety of contexts.

16.
Chem Commun (Camb) ; 55(6): 802-805, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30574643

RESUMO

Here we present 2shRNA, a shRNA-based nanobinder, which can simultaneously attack two therapeutic targets involved in drug resistance pathways and can additionally bind accessory molecules such as cell targeting peptides or fluorophores. We create 2shRNAs designed to specifically kill HER2+ breast cancer cells in the absence of a transfecting agent.


Assuntos
Nanoestruturas/química , RNA Interferente Pequeno/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Microscopia Confocal , Simulação de Dinâmica Molecular , Peptídeos/química , Peptídeos/metabolismo , RNA Interferente Pequeno/metabolismo , RNA Interferente Pequeno/uso terapêutico , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo
17.
J Biol Chem ; 293(46): 17888-17905, 2018 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-30262667

RESUMO

Newly discovered bacterial photoreceptors called CarH sense light by using 5'-deoxyadenosylcobalamin (AdoCbl). They repress their own expression and that of genes for carotenoid synthesis by binding in the dark to operator DNA as AdoCbl-bound tetramers, whose light-induced disassembly relieves repression. High-resolution structures of Thermus thermophilus CarHTt have provided snapshots of the dark and light states and have revealed a unique DNA-binding mode whereby only three of four DNA-binding domains contact an operator comprising three tandem direct repeats. To gain further insights into CarH photoreceptors and employing biochemical, spectroscopic, mutational, and computational analyses, here we investigated CarHBm from Bacillus megaterium We found that apoCarHBm, unlike monomeric apoCarHTt, is an oligomeric molten globule that forms DNA-binding tetramers in the dark only upon AdoCbl binding, which requires a conserved W-X 9-EH motif. Light relieved DNA binding by disrupting CarHBm tetramers to dimers, rather than to monomers as with CarHTt CarHBm operators resembled that of CarHTt, but were larger by one repeat and overlapped with the -35 or -10 promoter elements. This design persisted in a six-repeat, multipartite operator we discovered upstream of a gene encoding an Spx global redox-response regulator whose photoregulated expression links photooxidative and general redox responses in B. megaterium Interestingly, CarHBm recognized the smaller CarHTt operator, revealing an adaptability possibly related to the linker bridging the DNA- and AdoCbl-binding domains. Our findings highlight a remarkable plasticity in the mode of action of B12-based CarH photoreceptors, important for their biological functions and development as optogenetic tools.


Assuntos
Proteínas de Bactérias/metabolismo , Cobamidas/metabolismo , DNA Bacteriano/metabolismo , Fotorreceptores Microbianos/metabolismo , Proteínas Repressoras/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Bacillus megaterium , Proteínas de Bactérias/genética , Sítios de Ligação , DNA Bacteriano/genética , Regulação Bacteriana da Expressão Gênica , Regiões Operadoras Genéticas , Fotorreceptores Microbianos/genética , Regiões Promotoras Genéticas , Ligação Proteica , Domínios Proteicos , Multimerização Proteica , Proteínas Repressoras/genética , Raios Ultravioleta
18.
Nat Genet ; 50(10): 1352-1358, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30262815

RESUMO

Due to recent advances in experimental and theoretical approaches, the dynamic three-dimensional organization (3D) of the nucleus has become a very active area of research in life sciences. We now understand that the linear genome is folded in ways that may modulate how genes are expressed during the basic functioning of cells. Importantly, it is now possible to build 3D models of how the genome folds within the nucleus and changes over time (4D). Because genome folding influences its function, this opens exciting new possibilities to broaden our understanding of the mechanisms that determine cell fate. However, the rapid evolution of methods and the increasing complexity of data can result in ambiguity and reproducibility challenges, which may hamper the progress of this field. Here, we describe such challenges ahead and provide guidelines to think about strategies for shared standardized validation of experimental 4D nucleome data sets and models.


Assuntos
Núcleo Celular/genética , Conjuntos de Dados como Assunto/normas , Genoma , Genômica/métodos , Genômica/normas , Guias como Assunto , Núcleo Celular/química , Núcleo Celular/ultraestrutura , Cromossomos/química , Cromossomos/genética , Agregação de Dados , Bases de Dados Genéticas/normas , Humanos , Microscopia , Microscopia Eletrônica , Modelos Teóricos , Conformação de Ácido Nucleico , Mapeamento Físico do Cromossomo/métodos , Mapeamento Físico do Cromossomo/normas , Padrões de Referência
19.
Nucleic Acids Res ; 46(15): 7554-7565, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-29905860

RESUMO

We analysed the basic mechanisms of signal transmission in DNA and the origins of the allostery exhibited by systems such as the ternary complex BAMHI-DNA-GRDBD. We found that perturbation information generated by a primary protein binding event travels as a wave to distant regions of DNA following a hopping mechanism. However, such a structural perturbation is transient and does not lead to permanent changes in the DNA geometry and interaction properties at the secondary binding site. The BAMHI-DNA-GRDBD allosteric mechanism does not occur through any traditional models: direct (protein-protein), indirect (reorganization of the secondary site) readout or solvent-release. On the contrary, it is generated by a subtle and less common entropy-mediated mechanism, which might have an important role to explain other DNA-mediated cooperative effects.


Assuntos
DNA/química , Conformação de Ácido Nucleico , Conformação Proteica , Proteínas/química , Regulação Alostérica , Sítios de Ligação/genética , DNA/genética , DNA/metabolismo , Entropia , Simulação de Dinâmica Molecular , Ligação Proteica , Proteínas/metabolismo
20.
Nat Commun ; 9(1): 2032, 2018 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-29795225

RESUMO

Modification of SMN2 exon 7 (E7) splicing is a validated therapeutic strategy against spinal muscular atrophy (SMA). However, a target-based approach to identify small-molecule E7 splicing modifiers has not been attempted, which could reveal novel therapies with improved mechanistic insight. Here, we chose as a target the stem-loop RNA structure TSL2, which overlaps with the 5' splicing site of E7. A small-molecule TSL2-binding compound, homocarbonyltopsentin (PK4C9), was identified that increases E7 splicing to therapeutic levels and rescues downstream molecular alterations in SMA cells. High-resolution NMR combined with molecular modelling revealed that PK4C9 binds to pentaloop conformations of TSL2 and promotes a shift to triloop conformations that display enhanced E7 splicing. Collectively, our study validates TSL2 as a target for small-molecule drug discovery in SMA, identifies a novel mechanism of action for an E7 splicing modifier, and sets a precedent for other splicing-mediated diseases where RNA structure could be similarly targeted.


Assuntos
Imidazóis/farmacologia , Indóis/farmacologia , Atrofia Muscular Espinal/tratamento farmacológico , RNA Mensageiro/metabolismo , Processamento Alternativo , Animais , Animais Geneticamente Modificados , Drosophila , Avaliação Pré-Clínica de Medicamentos , Éxons/genética , Células HeLa , Humanos , Imidazóis/química , Imidazóis/uso terapêutico , Indóis/química , Indóis/uso terapêutico , Terapia de Alvo Molecular/métodos , Atrofia Muscular Espinal/genética , Fenótipo , Sítios de Splice de RNA , RNA Mensageiro/química , RNA Mensageiro/genética , Elementos Reguladores de Transcrição/efeitos dos fármacos , Proteína 2 de Sobrevivência do Neurônio Motor/genética
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