Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Transcriptional effects of TDP1 deficiency in non-replicating U2OS cells

ABSTRACT: Spinocerebellar ataxia with axonal neuropathy (SCAN1) is a rare recessive neurodegenerative syndrome associated with cerebellar atrophy and peripheral neuropathy. It is caused by a homozygous missense mutation in the tyrosyl-DNA phosphodiesterase-1 (TDP1) gene (A1478G). resulting in a substitution of histidine for arginine-493 (H493R) in the TDP1 catalytic site, leading to reduced TDP1 activity. How TDP1 H493R mutation promotes the SCAN1 phenotype, which is associated with the death of post-mitotic neurons, is unclear. We have generated models of osteosarcoma U2OS cells homozygous for TDP1 H493R employing the CRISPR-Cas9 technique (2 clones, named “1P” and “3.3”). Here, we have generated transcriptional genome wide profile in order to characterize differences in gene expression that are specific of TDP1-mutated clones.

ORGANISM(S): Homo sapiens

PROVIDER: GSE186693 | GEO | 2024/04/30

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Investigation of genetic compensation in tdp1-/- zebrafish embryos

Project description:Tdp1, tyrosyl-DNA phosphodiesterase 1, is an enzyme responsible for the repair of DNA breaks resulting from aberrant topoisomerase 1 activity, called Top1 cleavage complexes (Top1-CCs). Mutation of Tdp1 leads to a progressive neurodegenerative disorder spinocerebellar ataxia with axonal neuropathy 1 (SCAN1). We have generated tdp1-/- zebrafish as a model for SCAN1. The adult fish have a behavioral defect and hypersensitivity to camptothecin (CPT), a Top1 poison. Strikingly, the embryos do not show increased sensitivity to CPT, unlike any other reported vertebrate models, suggesting genetic compensation is at play at this stage. We thus carried out microarray analysis in CPT-treated zebrafish embryos to compare the gene expression profiles of tdp1WT and tdp1-/- genotypes. Gene expression analysis revealed 1,8111 genes that were differentially expressed: 1,071 were upregulated and 740 were downregulated. Sprtn and neil1, two potential compensation candidates were upregulated in the tdp1-/- embryos.

2022-04-19 | GSE148923 | GEO

TDP1 gene knockout effect on transcriptome

Project description:TDP1 is an enzyme that in humans is encoded by the TDP1 gene.[5][6][7] TDP1 is the protein involved in repairing stalled topoisomerase I-DNA complexes. We evaluated the effect of Tdp1 knockout in HEK293A cells on the gene expression.

2023-11-20 | GSE247361 | GEO

TDP1 mutation causing SCAN1 neurodegenerative syndrome hampers the repair of transcriptional DNA double-strand breaks

Project description:TDP1 removes transcription-blocking TOP1 cleavage complexes (TOP1ccs) and its inactivating H493R mutation causes the neurodegenerative syndrome SCAN1. However, the molecular mechanism underlying SCAN1 phenotype is unclear. Here, we generate human SCAN1 cell models using CRISPR/Cas9 and show that they accumulate TOP1ccs along with changes in gene expression and genomic distribution of R-loops. SCAN1 cells also accumulate transcriptional DNA double-strand breaks (DSBs) specifically in the G1 cell population due to increased DSB formation and lack of repair, both resulting from abortive removal of transcription-blocking TOP1ccs. Deficient TDP1 activity causes increased DSB production and the presence of mutated TDP1 protein hampers DSB repair by a TDP2-dependent back-up pathway. This study provides powerful models to study TDP1 functions under physiological and pathological conditions and unravels that a gain of function of the mutated TDP1 protein, which prevents DSB repair, rather than a loss of TDP1 activity itself, could contribute to SCAN1 pathogenesis.

2024-04-25 | GSE226263 | GEO

Up regulated Variant Surface Glycoproteins under TDP1 overexpression

Project description:Trypanosoma brucei parasites successfully evade the host immune system by periodically switching the dense coat of Variant Surface Glycoproteins (VSG) at the cell surface. Each parasite expresses VSGs in a monoallelic fashion that is tightly regulated. The consequences of exposing multiple VSGs during an infection in terms of antibody response and disease severity remain unknown. In this study, we overexpressed a high mobility group box protein, TDP1, which was sufficient to open the chromatin of silent VSG expression sites, to disrupt VSG monoallelic expression and to generate viable and healthy parasites with a mixed VSG coat. Mice infected with these parasites mounted a multi-VSG antibody response, which rapidly reduced parasitemia. Consequently, we observed a prolonged mice survival in which nearly 90% of the mice survived a 30-day period infection with undetectable parasitemia. Immunodeficient RAG2 knock-out mice were unable to control the infection with TDP1-overexpressing parasites, showing that the adaptive immune response is critical to reduce disease severity. This study shows that simultaneous exposure of multiple VSGs is highly detrimental for the parasite even at the very early stages of infection, suggesting that drugs that disrupt VSG monoallelic expression could be used to treat trypanosomiasis.

2019-09-13 | PXD014803 | Pride

Investigation of genetic compensation in tdp1-/- zebrafish embryos

Project description:Investigation of genetic compensation in tdp1-/- zebrafish embryos

| PRJNA626551 | ENA

tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase

Project description:Heterozygous mutations in six tRNA synthetase genes cause Charcot-Marie-Tooth (CMT) peripheral neuropathy. CMT-mutant glycyl- or tyrosyl-tRNA synthetases inhibit global protein synthesis by an unknown mechanism, independent of aminoacylation activity. We report that tRNAGly overexpression rescues protein synthesis and peripheral neuropathy phenotypes in Drosophila and mouse models of CMT caused by glycyl-tRNA synthetase (GlyRS) mutations (CMT2D). Kinetic experiments revealed that CMT-mutant GlyRS bind tRNAGly, but display markedly slow release rates. This tRNAGly sequestration may deplete the cellular tRNAGly pool, leading to insufficient glycyl-tRNAGly supply to the ribosome and translation deficit.

2021-09-07 | GSE160584 | GEO

Direct interaction of tyrosyl DNA phosphodiesterase 1 with DNA ligase III catalytic domain is regulated by phosphorylation of its flexible N-terminus

Project description:Tyrosyl DNA phosphodiesterase 1 (TDP1) and DNA Ligase III (LigIII) are key enzymes in nuclear and mitochondrial single-strand break (SSB) repair pathways whereby TDP1 removes the 3-tyrosine residue remaining after degradation of a trapped DNA topoisomerase 1. Here we define a direct interaction between TDP1 catalytic domain and LigIII DNA binding domain (DBD) that is regulated by conformational changes in the unstructured TDP1 N-terminal region induced by phosphorylation and/or alterations in amino acid sequence. Full-length and N-terminally truncated TDP1 are more effective at correcting the defect in SSB repair of TDP1 null cells compared with full-length TDP1 with amino acid substitutions of an N-terminal serine residue that is phosphorylated in response to DNA damage. TDP1 forms a stable complex with LigIII170-755, full-length LigIII as well as full-length LigIII alone and in complex with XRCC1. Homodimerization of LigIII BRCT domains links two LigIII-TDP1 heterodimers. Small angle X-ray scattering and negative stain electron microscopy combined with mapping of the interacting regions, identify a TDP1/LigIII compact dimer of heterodimers in which the two LigIII catalytic cores are positioned in the center, whereas two TDP1 molecules are located at the edges of the core complex formed by the LigIII DBD and the TDP1 catalytic domain flanked by highly flexible regions that can interact with other repair proteins and the SSB. As TDP1- LigIII repairs adducts caused by TOP1 cancer chemotherapy inhibitors, the defined interaction architecture and regulation informs on how this enzyme complex functions and is regulated in non-malignant and cancer cells.

2021-04-12 | MSV000087179 | MassIVE

TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts

Project description:Eukaryotic topoisomerase 1 (TOP1) regulates DNA topology to ensure efficient DNA replication and transcription. TOP1 is also a major driver of endogenous genome instability, particularly when its catalytic intermediate - a covalent TOP1-DNA adduct known as a TOP1 cleavage complex (TOP1cc) - is stabilised. TOP1ccs are highly cytotoxic and a failure to resolve them underlies the pathology of neurological disorders but is also exploited in cancer therapy where TOP1ccs are the target of widely used frontline anti-cancer drugs. A critical enzyme for TOP1cc resolution is the tyrosyl-DNA phosphodiesterase, TDP1, which hydrolyses the bond that links a tyrosine in the active site of TOP1 to a 3’ phosphate group on a single-stranded (ss)DNA break. However, TDP1 can only process small peptide fragments from ssDNA ends, raising the question of how the ~90 kDa TOP1 protein is processed upstream of TDP1. We find that TEX264 fulfils this role by forming a complex with the p97 ATPase and the SPRTN metalloprotease. We show that TEX264 recognises both unmodified and SUMO1-modifed TOP1 and initiates TOP1cc repair by recruiting p97 and SPRTN. TEX264 localises to the nuclear periphery, associates with DNA replication forks, and counteracts TOP1ccs during DNA replication. Altogether, our study elucidates the existence of a specialised repair complex required for upstream proteolysis of TOP1ccs and their subsequent resolution.

2020-03-13 | PXD017239 | Pride

Targeting ATP2B1 impairs PI3K/Akt/Forkhead box (Fox) transcription factor signaling and reduces SARS-COV-2 infection and replication

Project description:RNA-seq of human cells Edited using CRISPR vs parental and Unedited control. We identified a rare homozygous intronic variant in the ATP2B1 locus (rs111337717; chr12:89643729, T>C) that is associated with the severity of COVID-19 (i.e., symptomatic versus asymptomatic patients). Next, we employed CRISPR/Cas9 technology to develop the disease mutation observed in high-risk patients. Several edited single colonies were picked and expanded followed by DNA sequencing, and four clones with desired homozygous modifications were identified. The transcriptional profiles of N=4 C/C clones were compared then to those of T/T controls comprising one parental cell line and three unedited post-selection HEK293T cell clones.

2024-05-13 | E-MTAB-13916 | biostudies-arrayexpress

Cell of origin epigenetic priming determines susceptibility to Tet2 mutation

Project description:Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigated how the cell state preceding Tet2 mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we found that the epigenetic features of clones at similar differentiation status were highly heterogeneous and functionally responded differently to Tet2 mutation. Cell differentiation stage also influenced Tet2 mutation response indicating that the cell of origin's epigenome modulates clone-specific behaviors in CH. Molecular features associated with higher risk outcomes include Sox4 that sensitized cells to Tet2 inactivation, inducing dedifferentiation, altered metabolism and increasing the in vivo clonal output of mutant cells, as confirmed in primary GMP and HSC models. Our findings validate the hypothesis that epigenetic features can predispose specific clones for dominance, explaining why identical genetic mutations can result in different phenotypes.

1970-01-01 | MTBLS9914 | MetaboLights

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data