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PROVIDER: PRJEB63149 | ENA |
REPOSITORIES: ENA
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Project description:RNA Targets and Function of Topoisomerase 3β in Reducing Stress in Neuronal Physiology
| PRJNA1049014 | ENA
Project description:Topoisomerase 3β (Top3β) relaxes DNA and RNA and its dysregulation is implicated in various neurodevelopmental and cognitive disorders. We developed a novel protocol to isolate RNA targets of the topoisomerase without artificial cross-linking and used it to identify the RNA targets of Top3β. Lack of the enzymatic activity of Top3β affects gene expression of (pre)mRNAs with the characteristics described for the Top3β targets and we found evidence that this might also apply to several neurological diseases and cancers with which human Top3β was associated.
2023-12-07 | GSE249429 | GEO
Project description:Topoisomerases are crucial to solve DNA topological problems, but they have not been linked to RNA metabolism. Here we show that human topoisomerase 3β (Top3β) is an RNA topoisomerase that biochemically and genetically interacts with FMRP, a protein deficient in Fragile X syndrome and known to regulate translation of mRNAs important for neuronal function and autism. Notably, the FMRP-Top3β interaction is abolished by a disease-associated FMRP mutation, and several human genetic studies link Top3β mutation to schizophrenia and intellectual disability. Top3β binds multiple mRNAs encoded by genes with neuronal functions related to schizophrenia and autism. Expression of one such gene, ptk2/FAK, is reduced in neuromuscular junctions of Top3β mutant flies. Synapse formation is defective in Top3β mutant flies and mice, as observed in FMRP mutant animals. Our findings suggest that Top3β acts as an RNA topoisomerase and works with FMRP to promote expression of mRNAs critical for neurodevelopment and mental health.
2013-08-04 | GSE47502 | GEO
Project description:Glycogen synthase kinase-3β (GSK-3β) has been recently identified as an important regulator of stem cell function. In vitro studies show that GSK-3β inhibition delays proliferation of human haematopoietic progenitor cells while increasing numbers of late dividing multipotent progenitors. Gene expression analysis revealed that GSK-3β inhibition modulates the expression of a subset of genes that are transcriptional targets for cytokines. GSK-3β inhibition antagonised down-regulation of genes encoding cyclin dependent kinase inhibitor p57 and a member of the growth arrest and DNA damage 45 family, GADD45B as well as up-regulation of cyclin D1 by cytokines, providing a possible mechanism for the BIO-induced delay in cell cycle progression. Surprisingly, inhibition of GSK-3β earlier shown to prevent β-catenin degradation and promote the nuclear accumulation of β-catenin was not sufficient to activate its transcriptional targets in haematopoietic stem cells. GSK-3β inhibition up-regulated the expression of a several positive regulators of stem cell function suppressed during cytokine-induced proliferation. The data supports a clinical role for GSK-3β inhibition to improve engraftment efficiency of ex vivo expanded stem cells.
2010-03-26 | GSE21073 | GEO
Project description:Topoisomerase 3β (TOP3B) and TDRD3 form a dual-activity topoisomerase complex that interacts with FMRP and can change the topology of both DNA and RNA. Here, we investigated the post-transcriptional influence of TOP3B and associated proteins on mRNA translation and turnover. First, we discovered that in human HCT116 colon cancer cells, knock-out (KO) of TOP3B had similar effects on mRNA turnover and translation as did TDRD3-KO, while FMRP-KO resulted in rather distinct effects, indicating that TOP3B had stronger coordination with TDRD3 than FMRP in mRNA regulation. Second, we identified TOP3B-bound mRNAs in HCT116 cells; we found that while TOP3B did not directly influence the stability or translation of most TOP3B target mRNAs, it stabilized a subset of target mRNAs but had a more complex effect on translation--enhancing for some mRNAs whereas reducing for others. Interestingly, a point mutation that specifically disrupted TOP3B catalytic activity only partially recapitulated the effects of TOP3B-KO on mRNA stability and translation, suggesting that the impact of TOP3B on target mRNAs is only in part linked to its ability to change topology of mRNAs. Collectively, our data suggest that TOP3B-TDRD3 can regulate mRNA translation and turnover by mechanisms that are dependent and independent of topoisomerase activity.
2022-06-08 | GSE188574 | GEO
Project description:To survive under adverse conditions, plants form stress granules (SGs) to temporally store mRNA and halt translation as a primary response. Dysregulation in SG disassembly can have detrimental effects on plant survival after stress release, yet the underlying mechanism remains poorly understood. Using Arabidopsis as a model system, we demonstrated that the AP-3 subunit AP-3β participates in heat response independently of its conventional role in vacuolar transportinteracts with the SG core RNA-binding proteins TSN1/2 in vivo and in vitro. We also showed that AP-3β is rapidly recruited to SGs upon heat induction and plays a key role in SG disassembly after heat release. We also discovered thatGenetic evidences support that AP-3β serves as an adaptor to recruit the 19S regulatory particle (RP) of the proteasome to SGs upon heat induction. Notably, the 19S RP promotes SG disassembly through RP-associated deubiquitylation, independent of its proteolytic catalytic activity. This deubiquitylation process of SG components is crucial for translation reinitiation and growth recovery after heat release. Our findings shed light on the non-proteolytic catalytic function of the RP in regulating SG dynamics disassembly and reveal highlight the importance of endomembrane proteins in supporting RNA granule dynamics in plant cells.a non-degradation mechanism for cellular adaptation to environmental stresses.
2025-01-24 | PXD058194 | Pride
Project description:Topoisomerase 3b (Top3b) is the only dual-activity topoisomerase in animals that can change topology for both DNA and RNA, and facilitate transcription on DNA and translation on mRNAs. Top3b mutation has been linked to schizophrenia, autism, epilepsy, and cognitive impairment. However, whether and how Top3b mutations are causal to these disorders remain unclear. Here we show that Top3b knockout mice exhibit behavioral phenotypes related to psychiatric disorders and cognitive impairment, including increased anxiety and fear, abnormal social interactions, impaired context discrimination, and defective spatial learning and memory. In addition, these mice display deficits in adult hippocampal neurogenesis and synaptic plasticity. Notably, the brains of the mutant mice exhibit impaired global neuronal activity-dependent transcription in response to fear conditioning stress, and the affected genes include many that are critical for neuronal functions and mental health. Our data suggest that Top3b is essential for normal brain function in multiple domains, and defective neuronal activity-dependent transcription may be a mechanism by which Top3b deletion causes cognitive impairment and psychiatric disorders.
2020-05-22 | GSE145730 | GEO
Project description:RNA-directed DNA methylation (RdDM) is a transcriptional silencing mechanism mediated by small and long noncoding RNAs produced by the plant-specific RNA polymerases Pol IV and Pol V, respectively. Through a chemical genetics screen with a luciferase-based DNA methylation reporter, LUCL, we found that camptothecin, a compound with anti-cancer properties that targets DNA topoisomerase 1a (TOP1a) was able to de-repress LUCL by reducing its DNA methylation and H3K9 dimethylation (H3K9me2) levels. Further studies with Arabidopsis top1a mutants showed that TOP1a promotes RdDM by facilitating the production of Pol V-dependent long non-coding RNAs, AGONAUTE4 recruitment and H3K9me2 deposition at transposable elements (TEs). 5 small RNA libraries were sequenced
2014-07-08 | E-GEOD-50719 | biostudies-arrayexpress
Project description:RNA-directed DNA methylation (RdDM) is a transcriptional silencing mechanism mediated by small and long noncoding RNAs produced by the plant-specific RNA polymerases Pol IV and Pol V, respectively. Through a chemical genetics screen with a luciferase-based DNA methylation reporter, LUCL, we found that camptothecin, a compound with anti-cancer properties that targets DNA topoisomerase 1M-NM-1 (TOP1M-NM-1) was able to de-repress LUCL by reducing its DNA methylation and H3K9 dimethylation (H3K9me2) levels. Further studies with Arabidopsis top1M-NM-1 mutants showed that TOP1M-NM-1 promotes RdDM by facilitating the production of Pol V-dependent long non-coding RNAs, AGONAUTE4 recruitment and H3K9me2 deposition at transposable elements (TEs). ten bisufite libraries were sequenced
2014-07-07 | E-GEOD-50691 | biostudies-arrayexpress
Project description:Neuronal activity causes the rapid expression of immediate early genes that are crucial for experience driven changes to synapses, learning, and memory. Here, using both molecular and genome-wide next generation sequencing methods, we report that neuronal activity stimulation triggers the formation of DNA double strand breaks (DSBs) in the promoters of a subset of early-response genes, including Fos, Npas4, and Egr1. Generation of targeted DNA DSBs within Fos and Npas4 promoters is sufficient to induce their expression even in the absence of an external stimulus. Activity-dependent DSB formation is likely mediated by the type II topoisomerase, Topoisomerase IIb (Topo IIb), and knockdown of Topo IIb attenuates both DSB formation and early response gene expression following neuronal stimulation. Our results suggest that DSB formation is a physiological event that rapidly resolves topological constraints to early-response gene expression in neurons. Generation of sequencing data from ChIP-seq with antibodies against γH2AX and Topo IIβ after neuronal activity stimulation, and RNA-seq after etoposide treatment
2015-06-04 | E-GEOD-61887 | biostudies-arrayexpress