scholarly journals THE INTERACTION OF miR-4258, miR-3960, miR-211-3p AND miR-3155b WITH mRNAs GENES OF NON-POLYGLUTAMINE TRINUCLEOTIDE DISORDERS

2020 ◽  
Vol 1 (337) ◽  
pp. 25-32 ◽  
Author(s):  
Belkozhayev A.M. ◽  
Niyazova R.Ye.
Keyword(s):  
Binding Energy ◽  
Binding Sites ◽  
Trinucleotide Repeat ◽  
Neurological Diseases ◽  
Repeat Expansion ◽  
Binding Characteristics ◽  
Human Genes ◽  
Free Binding Energy ◽  
Nucleotide Repeats ◽  
Cug Repeats

Trinucleotide repeat expansion disorders constitute a group of dominantly inherited neurological diseases that are incurable and ultimately fatal. In the present work, miRNA binding sites were predicted by the MirTarget program. It was given characteristics of miRNAs binding sites in 5' and 3' UTR mRNAs genes of non-polyglutamine trinucleotide disorders with CGG, GCC, CUG repeats. Binding sites of 2567 miRNAs with mRNAs of 17494 human genes were determined. 206 genes with nucleotide repeats, mRNAs of which are bind with miRNA in the 5'UTR and 3'UTR, were observed. From thus, 2668 miRNAs binding sites are located in the 5'UTR, 3853 – in the 3'UTR with ΔG/ΔGm values equal to 85 % and more. It was found that 34 gene’s mRNA having trinucleotide (CGG\GCC\CUG) repeats were targets for miR-4258, miR-3960 miR-211-3p and miR-3155b. miR-4258 binds to mRNA of ADARB1, C11orf87 and CBFB genes with free binding energy - 93 kJ/mole and ΔG/ΔGm 91%, to mRNA of ARHGEF7, BCR, BRSK2 and C9orf91 genes with free binding energy - 91 kJ/mole and ΔG/ΔGm 89%. miR-3960 binds in GCC repeats to mRNA of ABCC1 and BLMH genes with free binding energy - 116 kJ/mole. miR-211-3p and miR-3155b interact with mRNA of ACACA and ANKRD13D genes in 5’-3’untranslated regions. Studying binding characteristics of miRNA and genes will help identify association of miRNAs with genes with trinucleotide repeats for recommending for the diagnosis of nucleotide repeat expansion disorders.

scholarly journals HDAC3 deacetylates the DNA mismatch repair factor MutSβ to stimulate triplet repeat expansions

2020 ◽  
Vol 117 (38) ◽  
pp. 23597-23605 ◽  
Author(s):  
Gregory M. Williams ◽  
Vasileios Paschalis ◽  
Janice Ortega ◽  
Frederick W. Muskett ◽  
James T. Hodgkinson ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Trinucleotide Repeat ◽  
Age Of Onset ◽  
Neurological Diseases ◽  
Inhibitory Effect ◽  
Repeat Expansion ◽  
Triplet Repeat ◽  
Lysine Residues ◽  
Repeat Expansions ◽  
Repair Factor

Trinucleotide repeat (TNR) expansions cause nearly 20 severe human neurological diseases which are currently untreatable. For some of these diseases, ongoing somatic expansions accelerate disease progression and may influence age of onset. This new knowledge emphasizes the importance of understanding the protein factors that drive expansions. Recent genetic evidence indicates that the mismatch repair factor MutSβ (Msh2-Msh3 complex) and the histone deacetylase HDAC3 function in the same pathway to drive triplet repeat expansions. Here we tested the hypothesis that HDAC3 deacetylates MutSβ and thereby activates it to drive expansions. The HDAC3-selective inhibitor RGFP966 was used to examine its biological and biochemical consequences in human tissue culture cells. HDAC3 inhibition efficiently suppresses repeat expansion without impeding canonical mismatch repair activity. Five key lysine residues in Msh3 are direct targets of HDAC3 deacetylation. In cells expressing Msh3 in which these lysine residues are mutated to arginine, the inhibitory effect of RGFP966 on expansions is largely bypassed, consistent with the direct deacetylation hypothesis. RGFP966 treatment does not alter MutSβ subunit abundance or complex formation but does partially control its subcellular localization. Deacetylation sites in Msh3 overlap a nuclear localization signal, and we show that localization of MutSβ is partially dependent on HDAC3 activity. Together, these results indicate that MutSβ is a key target of HDAC3 deacetylation and provide insights into an innovative regulatory mechanism for triplet repeat expansions. The results suggest expansion activity may be druggable and support HDAC3-selective inhibition as an attractive therapy in some triplet repeat expansion diseases.

scholarly journals The Role of the Immune System in Triplet Repeat Expansion Diseases

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Marta Olejniczak ◽  
Martyna O. Urbanek ◽  
Wlodzimierz J. Krzyzosiak
Keyword(s):  
Immune System ◽  
Trinucleotide Repeat ◽  
Inflammatory Responses ◽  
Neurological Diseases ◽  
Repeat Expansion ◽  
Cag Repeat ◽  
Triplet Repeat ◽  
Triplet Repeat Expansion ◽  
Polyglutamine Disorders ◽  
Intracellular Aggregates

Trinucleotide repeat expansion disorders (TREDs) are a group of dominantly inherited neurological diseases caused by the expansion of unstable repeats in specific regions of the associated genes. Expansion of CAG repeat tracts in translated regions of the respective genes results in polyglutamine- (polyQ-) rich proteins that form intracellular aggregates that affect numerous cellular activities. Recent evidence suggests the involvement of an RNA toxicity component in polyQ expansion disorders, thus increasing the complexity of the pathogenic processes. Neurodegeneration, accompanied by reactive gliosis and astrocytosis is the common feature of most TREDs, which may suggest involvement of inflammation in pathogenesis. Indeed, a number of immune response markers have been observed in the blood and CNS of patients and mouse models, and the activation of these markers was even observed in the premanifest stage of the disease. Although inflammation is not an initiating factor of TREDs, growing evidence indicates that inflammatory responses involving astrocytes, microglia, and the peripheral immune system may contribute to disease progression. Herein, we review the involvement of the immune system in the pathogenesis of triplet repeat expansion diseases, with particular emphasis on polyglutamine disorders. We also present various therapeutic approaches targeting the dysregulated inflammation pathways in these diseases.

scholarly journals Study of Endogen Substrates, Drug Substrates and Inhibitors Binding Conformations on MRP4 and Its Variants by Molecular Docking and Molecular Dynamics

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 1051
Author(s):  
Edgardo Becerra ◽  
Giovanny Aguilera-Durán ◽  
Laura Berumen ◽  
Antonio Romo-Mancillas ◽  
Guadalupe García-Alcocer
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Binding Energy ◽  
Binding Site ◽  
Binding Sites ◽  
Adenosine Monophosphate ◽  
Competitive Inhibitor ◽  
Umbrella Sampling ◽  
Coarse Grained ◽  
Nucleotide Polymorphisms

Multidrug resistance protein-4 (MRP4) belongs to the ABC transporter superfamily and promotes the transport of xenobiotics including drugs. A non-synonymous single nucleotide polymorphisms (nsSNPs) in the ABCC4 gene can promote changes in the structure and function of MRP4. In this work, the interaction of certain endogen substrates, drug substrates, and inhibitors with wild type-MRP4 (WT-MRP4) and its variants G187W and Y556C were studied to determine differences in the intermolecular interactions and affinity related to SNPs using protein threading modeling, molecular docking, all-atom, coarse grained, and umbrella sampling molecular dynamics simulations (AA-MDS and CG-MDS, respectively). The results showed that the three MRP4 structures had significantly different conformations at given sites, leading to differences in the docking scores (DS) and binding sites of three different groups of molecules. Folic acid (FA) had the highest variation in DS on G187W concerning WT-MRP4. WT-MRP4, G187W, Y556C, and FA had different conformations through 25 ns AA-MD. Umbrella sampling simulations indicated that the Y556C-FA complex was the most stable one with or without ATP. In Y556C, the cyclic adenosine monophosphate (cAMP) and ceefourin-1 binding sites are located out of the entrance of the inner cavity, which suggests that both cAMP and ceefourin-1 may not be transported. The binding site for cAMP and ceefourin-1 is quite similar and the affinity (binding energy) of ceefourin-1 to WT-MRP4, G187W, and Y556C is greater than the affinity of cAMP, which may suggest that ceefourin-1 works as a competitive inhibitor. In conclusion, the nsSNPs G187W and Y556C lead to changes in protein conformation, which modifies the ligand binding site, DS, and binding energy.

scholarly journals Secondary structural choice of DNA and RNA associated with CGG/CCG trinucleotide repeat expansion rationalizes the RNA misprocessing in FXTAS

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yogeeshwar Ajjugal ◽  
Narendar Kolimi ◽  
Thenmalarchelvi Rathinavelan
Keyword(s):  
Rna Binding ◽  
Trinucleotide Repeat ◽  
Rna Binding Proteins ◽  
Fragile X ◽  
Repeat Expansion ◽  
Mobility Shift ◽  
Cgg Repeat ◽  
Dna And Rna ◽  
Structural Choice ◽  
Sense Strand

AbstractCGG tandem repeat expansion in the 5′-untranslated region of the fragile X mental retardation-1 (FMR1) gene leads to unusual nucleic acid conformations, hence causing genetic instabilities. We show that the number of G…G (in CGG repeat) or C…C (in CCG repeat) mismatches (other than A…T, T…A, C…G and G…C canonical base pairs) dictates the secondary structural choice of the sense and antisense strands of the FMR1 gene and their corresponding transcripts in fragile X-associated tremor/ataxia syndrome (FXTAS). The circular dichroism (CD) spectra and electrophoretic mobility shift assay (EMSA) reveal that CGG DNA (sense strand of the FMR1 gene) and its transcript favor a quadruplex structure. CD, EMSA and molecular dynamics (MD) simulations also show that more than four C…C mismatches cannot be accommodated in the RNA duplex consisting of the CCG repeat (antisense transcript); instead, it favors an i-motif conformational intermediate. Such a preference for unusual secondary structures provides a convincing justification for the RNA foci formation due to the sequestration of RNA-binding proteins to the bidirectional transcripts and the repeat-associated non-AUG translation that are observed in FXTAS. The results presented here also suggest that small molecule modulators that can destabilize FMR1 CGG DNA and RNA quadruplex structures could be promising candidates for treating FXTAS.

scholarly journals Trinucleotide repeat expansion length as a predictor of the clinical progression of Fuchs’ Endothelial Corneal Dystrophy

PLoS ONE ◽  
2019 ◽  
Vol 14 (1) ◽  
pp. e0210996 ◽  
Author(s):  
Yu Qiang Soh ◽  
Gary Peh Swee Lim ◽  
Hla Myint Htoon ◽  
Xin Gong ◽  
V. Vinod Mootha ◽  
...  
Keyword(s):  
Trinucleotide Repeat ◽  
Corneal Dystrophy ◽  
Repeat Expansion ◽  
Clinical Progression ◽  
Trinucleotide Repeat Expansion

scholarly journals REscan: inferring repeat expansions and structural variation in paired-end short read sequencing data

2020 ◽  
Author(s):  
Russell Lewis McLaughlin
Keyword(s):  
Structural Variation ◽  
Sequence Data ◽  
Neurological Diseases ◽  
Repeat Expansion ◽  
Sequencing Data ◽  
Short Read ◽  
Short Read Sequencing ◽  
Repeat Expansions ◽  
Paired End Sequencing

Abstract Motivation Repeat expansions are an important class of genetic variation in neurological diseases. However, the identification of novel repeat expansions using conventional sequencing methods is a challenge due to their typical lengths relative to short sequence reads and difficulty in producing accurate and unique alignments for repetitive sequence. However, this latter property can be harnessed in paired-end sequencing data to infer the possible locations of repeat expansions and other structural variation. Results This article presents REscan, a command-line utility that infers repeat expansion loci from paired-end short read sequencing data by reporting the proportion of reads orientated towards a locus that do not have an adequately mapped mate. A high REscan statistic relative to a population of data suggests a repeat expansion locus for experimental follow-up. This approach is validated using genome sequence data for 259 cases of amyotrophic lateral sclerosis, of which 24 are positive for a large repeat expansion in C9orf72, showing that REscan statistics readily discriminate repeat expansion carriers from non-carriers. Availabilityand implementation C source code at https://github.com/rlmcl/rescan (GNU General Public Licence v3).

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