Inhibition of the ATM kinase rescues planarian regeneration after lethal radiation
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ABSTRACT:
PROVIDER: PRJNA787217 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17168138_1.fastq.gz | Fastqsanger.gz | |||
| SRR17168138_2.fastq.gz | Fastqsanger.gz | |||
| SRR17168140_1.fastq.gz | Fastqsanger.gz | |||
| SRR17168140_2.fastq.gz | Fastqsanger.gz | |||
| SRR17168142_1.fastq.gz | Fastqsanger.gz |
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Project description:As stem cells divide, they acquire mutations that can be passed on to daughter cells. To mitigate potentially deleterious outcomes, cells activate the DNA damage response (DDR) network, which governs several potential cellular outcomes following DNA damage, including repairing DNA or undergoing apoptosis. At the helm of the DDR are three PI3-like kinases including Ataxia Telangiectasia Mutated (ATM). We report here that knockdown of ATM in planarian flatworms enables stem cells to withstand lethal doses of radiation which would otherwise induce cell death. In this context, stem cells circumvent apoptosis, replicate their DNA, and recover function using homologous recombination-mediated DNA repair. Despite radiation exposure, atm knockdown animals survive long-term and regenerate new tissues. These effects occur independently of ATM’s canonical downstream effector p53. Together, our results demonstrate that in planarians, ATM regulates radiation-induced apoptosis. This acute, ATM-dependent apoptosis is a key determinant of long-term animal survival. Our results suggest that inhibition of ATM in these organisms could therefore potentially favor cell survival after radiation without obvious effects on stem cell behavior.
2022-12-25 | GSE190454 | GEO
Project description:As stem cells divide, they acquire mutations that can be passed on to daughter cells. To mitigate potentially deleterious outcomes, cells activate the DNA damage response (DDR) network, which governs several cellular outcomes following DNA damage, including repairing DNA or undergoing apoptosis. At the helm of the DDR are three PI3-like kinases including Ataxia-Telangiectasia Mutated (ATM). We report here that knockdown of ATM in planarian flatworms enables stem cells to withstand lethal doses of radiation which would otherwise induce cell death. In this context, stem cells circumvent apoptosis, replicate their DNA, and recover function using homologous recombination-mediated DNA repair. Despite radiation exposure, atm knockdown animals survive long-term and regenerate new tissues. These effects occur independently of ATM's canonical downstream effector p53. Together, our results demonstrate that in planarians, ATM promotes radiation-induced apoptosis. This acute, ATM-dependent apoptosis is a key determinant of long-term animal survival. Our results suggest that inhibition of ATM in these organisms could, therefore, potentially favor cell survival after radiation without obvious effects on stem cell behavior.
| S-EPMC10157310 | biostudies-literature
Project description:As stem cells divide, they acquire mutations that can be passed on to daughter cells. To mitigate potentially deleterious outcomes, cells activate the DNA damage response (DDR) network, which governs several potential cellular outcomes following DNA damage, including repairing DNA or undergoing apoptosis. At the helm of the DDR are three PI3-like kinases including Ataxia Telangiectasia Mutated (ATM). We report here that knockdown of ATM in planarian flatworms enables stem cells to withstand lethal doses of radiation which would otherwise induce cell death. In this context, stem cells circumvent apoptosis, replicate their DNA, and recover function using homologous recombination-mediated DNA repair. Despite radiation exposure, atm knockdown animals survive long-term and regenerate new tissues. These effects occur independently of ATM's canonical downstream effector p53. Together, our results demonstrate that in planarians, ATM promotes radiation-induced apoptosis. This acute, ATM-dependent apoptosis is a key determinant of long-term animal survival. Our results suggest that inhibition of ATM in these organisms could therefore potentially favor cell survival after radiation without obvious effects on stem cell behavior.
| S-SCDT-10_15252-EMBR_202256112 | biostudies-other
Project description:Regeneration is the regrowth of damaged tissues or organs, a vital mechanism in response to damages from primitive organisms to higher mammals. Planarian possesses active whole-body regenerative capability owning to its vast reservoir of adult stem cells, neoblasts, providing an ideal model to delineate the underlying mechanisms for regeneration. RNA N6-methyladenosine (m6A) modification participates in many biological processes, including stem cell self-renewal and differentiation, in particular the regeneration of hematopoietic stem cells and axons. However, how m6A controls regeneration at the whole-organism level remains largely unknown. Here, we demonstrate that the depletion of m6A methyltransferase regulatory subunit wtap abolishes planarian regeneration, potentially through regulating genes related to cell-cell communication and cell cycle. Single-cell RNA-seq (scRNA-seq) analysis unveils that the wtap knockdown induces a unique type of neural progenitor-like cells (NP-like cells), characterized by specific expression of the cell-cell communication ligand grn. Intriguingly, the depletion of m6A-modified transcripts grn/cdk9 (or cdk7) axis rescues the defective regeneration of planarian caused by wtap knockdown. Overall, our study reveals an indispensable role of m6A modification in regulating whole-organism regeneration.
2023-04-28 | GSE202928 | GEO
Project description:Diffuse midline gliomas (DMGs) are lethal brain tumors characterized by inactivating p53 mutations and oncohistone H3.3K27M mutations that rewire the cellular response to genotoxic stress, presenting therapeutic opportunities. We used RCAS/tv-a retroviruses and Cre recombinase to inactivate p53 and induce K27M in the native H3f3a allele in a lineage- and spatially-directed manner, yielding primary mouse DMGs. Disruption of the DNA damage response kinase Ataxia-telangiectasia mutated (Atm) enhanced the efficacy of focal brain irradiation, extending mouse survival. This finding suggests that targeting ATM will enhance the efficacy of radiation therapy for p53-mutant DMG but not p53-wildtype DMG. We used spatial in situ transcriptomics and an allelic series of primary murine DMG models to identify transactivation-independent p53 activity as the key mediator of such radiosensitivity.
2023-11-04 | GSE246584 | GEO
Project description:Analysis of the effects of ATM loss on gene expression to identify causes of neurodegeneration. ATM levels were reduced ubiquitously via the temperature-sensitive ATM^8 allele, or via tissue-specific RNAi of ATM (ATMi) using the Gal4/UAS expression system in neurons (Elav-GAL4 and ElavC155-GAL4) or glial cells (Repo-GAL4). A 20-chip study using total RNA representing 2 replicates of 3 control genotypes (ATM^8/+, Repo-GAL4, and ElavC155-GAL4) and 3 experimental genotypes (ATM^8/ATM^8, Repo-ATMi, ElavC155-ATMi), and 4 replicates each of a control (Elav-GAL4) and experimental (Elav-ATMi) genotype
2011-12-10 | E-GEOD-34315 | biostudies-arrayexpress
Project description:Analysis of the effects of ATM loss on gene expression to identify causes of neurodegeneration. ATM levels were reduced ubiquitously via the temperature-sensitive ATM^8 allele, or via tissue-specific RNAi of ATM (ATMi) using the Gal4/UAS expression system in neurons (Elav-GAL4 and ElavC155-GAL4) or glial cells (Repo-GAL4).
2011-12-10 | GSE34315 | GEO
Project description:Diffuse midline gliomas (DMGs) are lethal brain tumors characterized by p53-inactivating mutations and oncohistone H3.3K27M mutations that rewire the cellular response to genotoxic stress. Using RCAS/tv-a retroviruses and Cre recombinase to inactivate p53 and induce native H3.3K27M mutations in a lineage- and spatially-directed manner, we generated primary mouse tumors that recapitulate human DMG. Disrupting ataxia-telangiectasia mutated kinase (ATM) enhanced the efficacy of radiation therapy in murine and patient-derived DMG models, increasing survival. Microscopy-based in situ sequencing was used to spatially resolve transcriptional profiles in >750,000 single cells with or without ATM disruption and radiation therapy, revealing altered immune-neoplastic and endothelial cell interactions after treatment. An allelic series of primary murine DMG models with different p53 mutations confirmed that transactivation-independent p53 activity is a key mediator of radiosensitivity after ATM disruption. Our findings contribute primary DMG mouse models with deep profiling and reveal the mechanisms of treatment response to an actionable therapeutic strategy.
2025-06-16 | GSE284759 | GEO
Project description:The head-regeneration transcriptome of the planarian Schmidtea mediterranea
2011-07-15 | E-MTAB-607 | biostudies-arrayexpress
Project description:Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by neuronal degeneration, telangiectasias, acute cancer predisposition, and hypersensitivity to ionizing radiation (IR). The gene defective in AT, ATM (for AT-mutated), encodes a protein, pATM that has been found to have IR-inducible kinase activity. Cells from individuals with AT exhibit severely attenuated cell cycle checkpoints in response to gamma radiation exposure. pATM has been hypothesized to act as part of a complex that senses DNA damage, in particular, DNA double strand breaks. We are studying the pATM-dependent gene expression responses to a dose of 1.5 Gy radiation in lymphoblastoid cell lines from multiple individuals with either wild type or mutated ATM. The gene expression analyses were performed on Agilent Human 1A Oligo chips containing approximately 16,000 60mer probes. We identified a set of genes whose gene expression changes are ATM-dependent following exposure to 1.5 Gy IR. This set of genes was tested by real time quantitative PCR analysis. The study consists of one dose group - 1.5 Gray gamma radiation. Samples were collected 6 hr following irradiation (treated) or mock irradiation (controls) for each culture. Each culture has a treated sample and a control sample. There are cultures from 6 wild-type ATM individuals and cultures from 6 individuals that are ATM-deficient, for a total of 12 cultures. Hybridizations compared RNA extracted from each individual culture's treated sample against its corresponding control sample, and were performed as dye-flip duplicates (1 replicate in each direction). Hybridizations were performed on the Human 1A Oligo Chips using low input, direct labeling at Paradigm Genetics Laboratory. Microarray scanning was performed with the Agilent G2565AA Scanner. Paradigm Standard Operating Procedures were followed for quality analysis, sample labeling, microarray hybridization and washing, scanning, image analysis and initial data analysis.
2013-12-02 | E-GEOD-19287 | biostudies-arrayexpress