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Evidence for toxic CAG trinucleotide repeats contributing to Huntington’s disease though RNA interference

ABSTRACT: Mutant huntingtin CAG trinucleotide repeat mimetic hairpins are loaded into the RISC and kill cells through RNAi

ORGANISM(S): synthetic construct

PROVIDER: GSE201694 | GEO | 2022/04/27

REPOSITORIES: GEO

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Evidence for toxic CAG trinucleotide repeats contributing to Huntington’s disease though RNA interference

Project description:Mutant huntingtin CAG trinucleotide repeat mimetic hairpins are loaded into the RISC and kill cells through RNAi

2022-04-27 | GSE201692 | GEO

Evidence for toxic CAG trinucleotide repeats contributing to Huntington’s disease though RNA interference

Project description:Mutant huntingtin CAG trinucleotide repeat mimetic hairpins are loaded into the RISC and kill cells through RNAi

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Evidence for toxic CAG trinucleotide repeats contributing to Huntington’ease though RNA interference II

Project description:Evidence for toxic CAG trinucleotide repeats contributing to Huntington’ease though RNA interference II

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Evidence for toxic CAG trinucleotide repeats contributing to Huntington’ease though RNA interference I

Project description:Evidence for toxic CAG trinucleotide repeats contributing to Huntington’ease though RNA interference I

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Transcription profiling of mouse cerebellum cells containing expanded or normal CAG trinucleotide repeats in the coding region for TATA-binding protein (TBP)

Project description:Transcription profiles were obtained for 2-month old mice containing an expanded or normal CAG trinucleotide repeat in the coding region for TATA-binding protein (TBP). Three different genotypes were used : TBP-13Q (normal), TBP-71Q (71 repeats), and TBP-105Q (105 repeats). Two lines of TBP-71Q (lines 16 and 27) were used in these experiments. <br><br> The 71Q and 105Q mice express a mutant version of the protein (TBP) and faithfully model the disease SCA17 (spinocerebellar ataxia-17, huntington disease-like 4, HDL4). <br><br> The constructs containing mixed CAG/CAA trinucleotide repeats (and encoding polyglutamine tracts) of variable length were made using a previously described method (Michalik A et al., Biotechniques, 2001). Briefly, synthetic CAG/CAA oligonucleotides were subcloned into a cDNA construct of the normal mouse (13 CAG/CAA) TBP gene. Because of the mixed nature of the repeat, its length is stable in mitotic and meiotic transmission.

2007-11-09 | E-MEXP-1313 | biostudies-arrayexpress

Length-dependent energetics of (CTG)n and (CAG)n trinucleotide repeats.

Project description:Trinucleotide repeats are involved in a number of debilitating diseases such as myotonic dystrophy. Twelve to seventy-five base-long (CTG)n oligodeoxynucleotides were analysed using a combination of biophysical [UV-absorbance, circular dichroism and differential scanning calorimetry (DSC)] and biochemical methods (non-denaturing gel electrophoresis and enzymatic footprinting). All oligomers formed stable intramolecular structures under near physiological conditions with a melting temperature that was only weakly dependent on oligomer length. Thermodynamic analysis of the denaturation process by UV-melting and calorimetric experiments revealed an unprecedented length-dependent discrepancy between the enthalpy values deduced from model-dependent (UV-melting) and model-independent (calorimetry) experiments. Evidence for non-zero molar heat capacity changes was also derived from the analysis of the Arrhenius plots and DSC profiles. Such behaviour is analysed in the framework of an intramolecular 'branched-hairpin' model, in which long CTG oligomers do not fold into a simple long hairpin-stem intramolecular structure, but allow the formation of several independent folding units of unequal stability. We demonstrate that, for sequences ranging from 12 to 25 CTG repeats, an intramolecular structure with two loops is formed which we will call 'bis-hairpin'. Similar results were also found for CAG oligomers, suggesting that this observation may be extended to various trinucleotide repeats-containing sequences.

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Studies on Copper and A?1-16-Induced Conformational Changes in CAG/CTG Trinucleotide Repeats Sequence.

Project description:DNA conformation and stability are critical for the normal cell functions, which control many cellular processes in life, such as replication, transcription, DNA repair, etc. The accumulation of amyloid-? peptide (A?) and Copper (Cu) are the etiological factors for neurodegenerative diseases and hypothesized that they can cause DNA instability. In the current investigation, we studied copper and A?1-16 induced conformation and stability changes in CAG/CTG sequences and found alterations from B-DNA to altered B-conformation. Further, the interaction of the copper and A?1-16 with CAG/CTG sequences was studied by molecular docking modeling and results indicated that the interaction of copper and A?1-16 was through the hydrogen bond formation between adenine, guanine, and cytocine. This study illustrates the role of the copper and A?1-16 in modulating the DNA conformation and stability.

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Structure and Dynamics of DNA and RNA Double Helices of CAG and GAC Trinucleotide Repeats.

Project description:CAG trinucleotide repeats are known to cause 10 late-onset progressive neurodegenerative disorders as the repeats expand beyond a threshold, whereas GAC repeats are associated with skeletal dysplasias and expand from the normal five to a maximum of seven repeats. The TR secondary structure is believed to play a role in CAG expansions. We have carried out free energy and molecular dynamics studies to determine the preferred conformations of the A-A noncanonical pairs in (CAG)n and (GAC)n trinucleotide repeats (n = 1, 4) and the consequent changes in the overall structure of the RNA and DNA duplexes. We find that the global free energy minimum corresponds to A-A pairs stacked inside the core of the helix with anti-anti conformations in RNA and (high-anti)-(high-anti) conformations in DNA. The next minimum corresponds to anti-syn conformations, whereas syn-syn conformations are higher in energy. Transition rates of the A-A conformations are higher for RNA than DNA. Mechanisms for these various transitions are identified. Additional structural and dynamical aspects of the helical conformations are explored, with a focus on contrasting CAG and GAC duplexes. The neutralizing ion distribution around the noncanonical pairs is described.

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Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells.

Project description:Trinucleotide repeat (TNR) expansions in the genome cause a number of degenerative diseases. A prominent TNR expansion involves the triplet CAG in the huntingtin (HTT) gene responsible for Huntington's disease (HD). Pathology is caused by protein and RNA generated from the TNR regions including small siRNA-sized repeat fragments. An inverse correlation between the length of the repeats in HTT and cancer incidence has been reported for HD patients. We now show that siRNAs based on the CAG TNR are toxic to cancer cells by targeting genes that contain long reverse complementary TNRs in their open reading frames. Of the 60 siRNAs based on the different TNRs, the six members in the CAG/CUG family of related TNRs are the most toxic to both human and mouse cancer cells. siCAG/CUG TNR-based siRNAs induce cell death in vitro in all tested cancer cell lines and slow down tumor growth in a preclinical mouse model of ovarian cancer with no signs of toxicity to the mice. We propose to explore TNR-based siRNAs as a novel form of anticancer reagents.

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Atomic resolution structure of CAG RNA repeats: structural insights and implications for the trinucleotide repeat expansion diseases.

Project description:CAG repeats occur predominantly in the coding regions of human genes, which suggests their functional importance. In some genes, these sequences can undergo pathogenic expansions leading to neurodegenerative polyglutamine (poly-Q) diseases. The mutant transcripts containing expanded CAG repeats possibly contribute to pathogenesis in addition to the well-known pathogenic effects of mutant proteins. We have analysed two crystal forms of RNA duplexes containing CAG repeats: (GGCAGCAGCC)(2). One of the structures has been determined at atomic resolution (0.95 Å) and the other at 1.9 Å. The duplexes include non-canonical A-A pairs that fit remarkably well within a regular A-helix. All the adenosines are in the anti-conformation and the only interaction within each A-A pair is a single C2-H2···N1 hydrogen bond. Both adenosines in each A-A pair are shifted towards the major groove, although to different extents; the A which is the H-bond donor stands out more (the 'thumbs-up' conformation). The main effect on the helix conformation is a local unwinding. The CAG repeats and the previously examined CUG structures share a similar pattern of electrostatic charge distribution in the minor groove, which could explain their affinity for the pathogenesis-related MBNL1 protein.

| S-EPMC3001072 | biostudies-literature

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