Tau affects P53 function and cell fate during the DNA damage response
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB33642 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR3449600_1.fastq.gz | Fastqsanger.gz | |||
| ERR3449600_2.fastq.gz | Fastqsanger.gz | |||
| ERR3449610_1.fastq.gz | Fastqsanger.gz | |||
| ERR3449610_2.fastq.gz | Fastqsanger.gz | |||
| ERR3449620_1.fastq.gz | Fastqsanger.gz |
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Project description:Cells are constantly exposed to DNA damaging insults. To protect the organism, cells developed a complex molecular response coordinated by P53, the master regulator of DNA repair, cell division and cell fate. DNA damage accumulation and abnormal cell fate decision may represent a pathomechanism shared by aging-associated disorders such as cancer and neurodegeneration. Here, we examined this hypothesis in the context of tauopathies, a neurodegenerative disorder group characterized by Tau protein deposition. For this, the response to an acute DNA damage was studied in neuroblastoma cells with depleted Tau, as a model of loss-of-function. Under these conditions, altered P53 stability and activity result in reduced cell death and increased cell senescence. This newly discovered function of Tau involves abnormal modification of P53 and its E3 ubiquitin ligase MDM2. Considering the medical need with vast social implications caused by neurodegeneration and cancer, our study may reform our approach to disease-modifying therapies.
| S-EPMC7237658 | biostudies-literature
Project description:After DNA damage, cells activate p53, a tumor suppressor gene, and select a cell fate (e.g., DNA repair, cell cycle arrest, or apoptosis). Recently, a p53 oscillatory behavior was observed following DNA damage. However, the relationship between this p53 oscillation and cell-fate selection is unclear. Here, we present a novel model of the DNA damage signaling pathway that includes p53 and whole cell cycle regulation and explore the relationship between p53 oscillation and cell fate selection. The simulation run without DNA damage qualitatively realized experimentally observed data from several cell cycle regulators, indicating that our model was biologically appropriate. Moreover, the comprehensive sensitivity analysis for the proposed model was implemented by changing the values of all kinetic parameters, which revealed that the cell cycle regulation system based on the proposed model has robustness on a fluctuation of reaction rate in each process. Simulations run with four different intensities of DNA damage, i.e. Low-damage, Medium-damage, High-damage, and Excess-damage, realized cell cycle arrest in all cases. Low-damage, Medium-damage, High-damage, and Excess-damage corresponded to the DNA damage caused by 100, 200, 400, and 800 J/m(2) doses of UV-irradiation, respectively, based on expression of p21, which plays a crucial role in cell cycle arrest. In simulations run with High-damage and Excess-damage, the length of the cell cycle arrest was shortened despite the severe DNA damage, and p53 began to oscillate. Cells initiated apoptosis and were killed at 400 and 800 J/m(2) doses of UV-irradiation, corresponding to High-damage and Excess-damage, respectively. Therefore, our model indicated that the oscillatory mode of p53 profoundly affects cell fate selection.
2024-09-02 | BIOMD0000000939 | BioModels
Project description:Neuronal excitotoxicity induced by aberrant excitation of glutamatergic receptors contributes to brain damage in stroke. Here, we show that tau-deficient (tau-/-) mice are profoundly protected from excitotoxic brain damage and neurological deficits following experimental stroke, using a middle cerebral artery occlusion (MCAO) with reperfusion model. Mechanistically, we show that this protection is due to site-specific inhibition of glutamate-induced and Ras/ERK-mediated toxicity by accumulation of Ras-inhibiting SynGAP1, which resides in a post-synaptic complex with tau. Accordingly, reducing SynGAP1 levels in tau-/- mice abolished the protection from pharmacologically induced excitotoxicity and MCAO-induced brain damage. Conversely, over-expression of SynGAP1 prevented excitotoxic ERK activation in wild-type neurons. Our findings suggest that tau mediates excitotoxic Ras/ERK signaling by controlling post-synaptic compartmentalization of SynGAP1.
2017-09-01 | GSE45703 | GEO
Project description:Alzheimer’s disease (AD) is the most prevalent form of neurodegeneration. Despite the well-established link between tau aggregation and clinical progression, the major pathways driven by this protein to intrinsically damage neurons are incompletely understood. To model AD-relevant neurodegeneration driven by tau, we overexpressed non-mutated human tau in primary mouse neurons and observed substantial axonal degeneration and cell death, a process accompanied by activated caspase 3. Mechanistically, we detected deformation of the nuclear envelope and increased DNA damage response in tau-expressing neurons. Gene profiling analysis further revealed significant alterations in the mitogen-activated protein kinase (MAPK) pathway; moreover, inhibitors of dual leucine zipper kinase (DLK) and c-Jun N-terminal kinase (JNK) were effective in alleviating wild-type human tau-induced neurodegeneration. In contrast, mutant P301L human tau was less toxic to neurons, despite causing comparable DNA damage. Axonal DLK activation induced by wild-type tau potentiated the impact of DNA damage response, resulting in overt neurotoxicity. In summary, we have established a cellular tauopathy model highly relevant to AD and identified a functional synergy between the MAPK-DLK axis and DNA damage response in the neuronal degenerative process.
2023-11-15 | GSE246259 | GEO
Project description:DNA damage has been implicated in neurodegenerative disorders, including Alzheimer’s disease and other tauopathies, but the consequences of genotoxic stress to postmitotic neurons are poorly understood. Here we demonstrate that p53, a key mediator of the DNA damage response, plays a neuroprotective role in a Drosophila model of tauopathy. Further, through a whole-genome ChIP-chip analysis we identify genes controlled by p53 in postmitotic neurons. We genetically validate a specific pathway, synaptic function, in p53-mediated neuroprotection. We then demonstrate that the control of synaptic genes by p53 is conserved in mammals. Collectively, our results implicate synaptic function as a central target in p53-dependent protection from neurodegeneration. 4 samples: tau vs. control
2015-01-06 | E-GEOD-40418 | biostudies-arrayexpress
Project description:Long noncoding RNAs (lncRNAs) are prevalent genes with frequently exquisite regulation but mostly unknown functions. Here we demonstrate a role of lncRNAs in guiding signal transduction. DNA damage activates transcription of DINO (Damage Induced NOncoding) via p53. DINO knockdown blocks DNA damage-induced gene expression and cell cycle arrest. Conversely, enforced expression of DINO activates damage signaling without DNA damage. DINO binds p53 and selectively promotes SET7 methylation of p53 at lysine 372 over other substrates, which stabilizes p53 in an auto-amplification loop. Our results suggest that inducible lncRNA can achieve catalysis-like effects to rewire cellular signaling networks. RNA was isolated from human fetal lung fibroblasts, HCT116 p53+/+, or HCT116 p53-/- cells treated with doxorubicin or sham for 26 hours. Human fetal lung fibroblasts were transfected with siRNAs targeting DINO or non-targeting control and subsequently treated with doxorubicin for 26 hours.
2012-11-20 | E-GEOD-42368 | biostudies-arrayexpress
Project description:The tumor suppressors p53 and HIPK2 play a central role in cell fate decision-making upon DNA damage and regulate cancer cell chemosensitivity. Here we identify the adaptor protein Deleted in Azoospermia-associated protein 2 (DAZAP2) as a novel player in the DNA damage-induced p53 response. Knock-down or genetic deletion of DAZAP2 potentiates cancer cell chemosensitivity in vitro and in vivo. In unstressed cells, DAZAP2 stimulates HIPK2 ubiquitination and degradation through interaction with HIPK2 and the ubiquitin ligase SIAH1. After chemotherapeutic drug-induced DNA damage, DAZAP2 accumulates in the cell nucleus, which is regulated through site-specific phosphorylation by HIPK2. Nuclear DAZAP2 interacts with p53 response elements and specifies p53 target gene expression by modulating a select subset of p53 target genes. Mechanistically, DAZAP2 forms a complex with p53 and modulates target gene expression in association with HDAC1. Our findings identify DAZAP2 as a novel regulator of the p53 response and cancer cell chemosensitivity.
2021-02-10 | GSE154146 | GEO
Project description:Long noncoding RNAs (lncRNAs) are prevalent genes with frequently exquisite regulation but mostly unknown functions. Here we demonstrate a role of lncRNAs in guiding signal transduction. DNA damage activates transcription of DINO (Damage Induced NOncoding) via p53. DINO knockdown blocks DNA damage-induced gene expression and cell cycle arrest. Conversely, enforced expression of DINO activates damage signaling without DNA damage. DINO binds p53 and selectively promotes SET7 methylation of p53 at lysine 372 over other substrates, which stabilizes p53 in an auto-amplification loop. Our results suggest that inducible lncRNA can achieve catalysis-like effects to rewire cellular signaling networks.
2012-11-20 | GSE42368 | GEO
Project description:Tau (MAPT) is a microtubule-associated protein causing frequent neurodegenerative diseases or inherited frontotemporal lobar degenerations. Emerging evidence for non-canonical functions of Tau in DNA protection and P53 regulation suggests its involvement in cancer. Indeed, Tau expression correlates with cancer-specific survival or response to microtubule therapeutics. These data may imply common molecular pathways involved in the pathogenesis of neurodegenerative disorders and cancer. To bring new evidence that Tau represents a key protein in cancer, we present an in silico pan-cancer analysis of MAPT transcriptomic profile in over 11000 clinical samples and over 1300 pre-clinical samples provided by the TCGA and the DEPMAP datasets respectively. We completed this analysis by exploring a possible interplay of MAPT with wild-type or mutated P53. Then, we calculated the impact of MAPT expression on clinical outcome and drug response. Overall, the results support a relevant role of the MAPT gene in several cancer types, although the contribution of Tau to cancer appears to very much depend on the cellular context.
2022-11-27 | E-MTAB-8166 | biostudies-arrayexpress
Project description:DNA-targeting drugs may damage DNA or chromatin. Many anti-cancer drugs do both, making difficult understanding their mechanism of actions. Using molecules causing DNA breaks without altering nucleosome structure (bleomycin) or destabilizing nucleosomes without damaging DNA (curaxin), we investigated consequences of DNA or chromatin damage in normal and tumor cells. As expected, DNA damage caused p53-dependent growth arrest followed by senescence. Chromatin damage caused higher p53 accumulation than DNA damage, but growth arrest was p53-independent and did not result in senescence. Chromatin damage activated transcription of multiple genes, including classical p53 targets, in a p53-independent manner. These activated genes, though they were not highly expressed, have chromatin organization around transcription start sites (TSS) characteristic for the most highly expressed genes and the highest level of paused RNA polymerase. We proposed that nucleosomes around TSS of these genes are the most sensitive to chromatin damage, and therefore nucleosome loss upon curaxin treatment enables transcription without assistance of sequence-specific transcriptional factors. We confirmed this by showing greater loss of nucleosomes around TSS of these genes upon curaxin treatment and activation of specific p53 reporter in p53-null cells by chromatin damaging agents, but not DNA damaging agents.
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