Cancer-associated synonymous mutations selectively target the p53 DNA damage response [ChIP-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE282501 | GEO | 2026/03/01
REPOSITORIES: GEO
Similar Datasets
Project description:Recent technical advances have facilitated studies on changes in mRNA structures in response to signaling pathways, but how mRNA structures relate to the function of the encoded protein remains poorly understood. Synonymous mutations (SMs) possess comparable oncogenic potential to missense mutations. Here we have taken advantage of two Cancer Associated SMs at codon 34 (CASM34) in the p53 mRNA to demonstrate the impact of the RNA structure on protein activity in response to DNA damage. In-cell RNA structural probing illustrates how CASM34s prevent DNA damage-induced p53 mRNA folding. Genome-wide transcriptomics show that CASM34 alters the expression of genes in the p53 DNA-damage response pathway. DNA ChIP-seq analysis reveals that p53 expressed from CASM34 has reduced promoter binding and reduced induction of p53 downstream target genes PUMA and 14-3-3-σ but not p21CDKN1A. These results demonstrate that CASM34s selectively target p53 activity towards downstream targets in the DNA damage response pathway by interfering with p53 mRNA folding.
2026-03-01 | GSE282500 | GEO
Project description:P53 inactivation occurs in about 50% of human cancers, where p53-driven p21 activity is devoid and p27 becomes essential for the establishment of the G1/S checkpoint upon DNA damage. Here, we show that the E2F1-responsive lncRNA LIMp27 selectively represses p27 expression and contributes to proliferation, tumorigenicity, and treatment resistance in p53-defective colon adenocarcinoma (COAD) cells. LIMp27 competes with p27 mRNA for binding to cytoplasmically localized hnRNA0, which otherwise stabilizes p27 mRNA leading to cell cycle arrest at the G0/G1 phase. In response to DNA damage, LIMp27 is upregulated in both wild-type and p53-mutant COAD cells, whereas cytoplasmic hnRNPA0 is only increased in p53-mutant COAD cells due to translocation from the nucleus. Moreover, high LIMp27 expression is associated with poor survival of p53-mutant but not wild-type p53 COAD patients. These results uncover a lncRNA mechanism that promotes p53-defective cancer pathogenesis and suggest that LIMp27 may constitute a target for the treatment of such cancers.
| MSV000090292 | MassIVE
Project description:Cancer-associated synonymous mutations selectively target the p53 DNA damage response [RNA-seq]
| PRJNA1189037 | ENA
Project description:Cancer-associated synonymous mutations selectively target the p53 DNA damage response [ChIP-seq]
| PRJNA1189036 | ENA
Project description:Comprehensive Model Description
Overview
This model simulates the cellular response to DNA damage under conditions of ATM/ATR deficiency—such as in ataxia telangiectasia—and predicts the potential benefits of drug repositioning with Omaveloxolone and spermidine. It integrates several interconnected modules: DNA damage production and repair, ATM/ATR–p53 signaling, NRF2/KEAP1 regulation, spermidine-induced autophagy (with additional positive modulation of ATR signaling), and downstream p53 effectors involved in cell fate decisions.
1. DNA Damage Production and Repair Module
Basal DNA Damage Production:
DNA damage is continuously generated at a constant rate, representing both endogenous processes and low-level environmental stress. This reaction acts as a source term for the DNA_damage species.
Repair Pathways:
Several mechanisms work to reduce DNA damage:
ATM-Mediated Repair: Active ATM facilitates the direct repair of DNA damage.
ATR-Mediated Repair: Active ATR, in cooperation with CHK1, repairs DNA damage.
NRF2-Mediated Repair: Active NRF2 triggers antioxidant responses that reduce DNA damage.
Autophagy-Mediated Repair: The autophagy pathway, induced by spermidine, repairs DNA damage in a saturable manner (modeled using Michaelis–Menten kinetics). This ensures that even a significant pulse of damage is only partially repaired, leaving a nonzero steady-state level.
2. ATM/ATR–p53 Signaling Module
ATM and ATR Activation:
DNA damage, along with a positive input from TOPBP1, converts inactive ATM and ATR to their active forms. Under ATM/ATR-deficient conditions (as in ataxia telangiectasia), the activation is severely reduced, resulting in higher levels of unrepaired DNA damage.
p53 Activation:
Both ATM_active and ATR_active phosphorylate and activate p53. Active p53 then acts as a central integrator of the DNA damage signal.
Regulatory Proteins:
HDAC4:
HDAC4 cycles between inactive and active states. Its active form can attenuate p53 activity.
TOPBP1:
TOPBP1 is activated in a DNA damage–dependent manner and helps promote ATR activation.
CK2:
CK2 is a constitutively active kinase that supports TOPBP1 activation.
3. NRF2/KEAP1 Module and Omaveloxolone
NRF2 Activation:
DNA damage stimulates the conversion of NRF2_inactive to NRF2_active. Active NRF2 enhances antioxidant defenses and promotes DNA repair.
KEAP1-Mediated Degradation:
Under normal conditions, KEAP1 targets NRF2_inactive for degradation, keeping NRF2 activity low.
Modulation by Omaveloxolone:
Omaveloxolone is modeled as a constant (boundary) species. It inhibits KEAP1’s activity, thereby reducing NRF2 degradation. This shifts the balance in favor of increased NRF2_active, which boosts the cell’s antioxidant and repair responses.
4. Spermidine-Induced Autophagy and Positive Modulation of ATR Signaling
Spermidine is modeled as a constant species and has two major effects:
Induction of Autophagy:
Spermidine promotes the conversion of Autophagy_inactive to Autophagy_active. The active autophagy machinery repairs DNA damage using a saturable (Michaelis–Menten) mechanism. This pathway helps clear DNA damage but is limited by its maximum capacity.
Enhancement of ATR Signaling:
Spermidine also positively modulates ATR signaling by enhancing the CK2-mediated activation of TOPBP1. In the model, the effective rate of TOPBP1 activation is increased proportionally to the concentration of spermidine. This is represented by a modulation factor, where the effective rate constant for TOPBP1 activation is multiplied by a term that increases with spermidine concentration. The boosted TOPBP1_active level in turn enhances ATR activation, partially compensating for the loss of ATM/ATR function.
5. Downstream p53 Targets: Cell Fate Decisions
Activated p53 regulates cell fate by inducing the production of several downstream effectors:
p21:
p21 is produced in response to p53 activation and is associated with cell cycle arrest and senescence. Its production is balanced by a degradation reaction.
BAX and PUMA:
Both BAX and PUMA are pro-apoptotic proteins. They are produced in proportion to p53_active and are subsequently degraded. Their relative levels help determine whether the cell will undergo apoptosis.
6. Reaction Kinetics (Qualitative Overview)
Mass-Action and Michaelis–Menten Kinetics:
Most reactions in the model are governed by mass-action kinetics. For example, activation and deactivation reactions (such as ATM activation by DNA damage or p53 activation by ATM/ATR) follow simple proportional relationships.
Saturable Repair Processes:
The autophagy-mediated DNA repair reaction uses Michaelis–Menten kinetics to reflect a saturation effect; when DNA damage is high, the repair rate approaches a maximum value, ensuring that not all damage is cleared immediately.
Modulatory Effects:
Spermidine increases the effective rate of TOPBP1 activation (and hence ATR activation) via a modulation term that is proportional to its concentration. Omaveloxolone reduces the degradation rate of NRF2 by inhibiting KEAP1.
Biological Implications and Model Utility
ATM/ATR Deficiency:
In ataxia telangiectasia, ATM/ATR functions are diminished, leading to increased DNA damage. The model simulates this scenario and examines how alternative pathways (NRF2-mediated repair, autophagy, and enhanced ATR signaling via spermidine) help mitigate the damage.
Drug Repositioning Predictions:
The model can be used to predict the outcomes of repositioning drugs:
Omaveloxolone is expected to stabilize NRF2, enhancing antioxidant defenses and reducing DNA damage.
Spermidine acts dually by promoting autophagy (with a saturable repair capacity) and by boosting ATR signaling via TOPBP1 activation.
Cell Fate Outcomes:
The downstream p53 targets (p21, BAX, and PUMA) serve as markers for cell cycle arrest/senescence and apoptosis. By simulating the dynamics of these proteins, the model can predict whether a cell is likely to survive, arrest its cycle, or undergo apoptosis based on the integrated response to DNA damage and drug interventions.
Conclusion
This detailed and comprehensive model integrates multiple layers of the cellular response to DNA damage in ATM/ATR-deficient conditions. It includes upstream damage sensing, multiple repair pathways (including direct kinase-mediated repair, antioxidant responses via NRF2, and autophagy-mediated repair), and downstream effectors that determine cell fate. Omaveloxolone and spermidine are modeled to specifically modulate the NRF2/KEAP1 pathway and ATR signaling (via TOPBP1 activation), respectively. This framework provides a robust platform for exploring drug repositioning strategies and predicting cellular outcomes in diseases such as ataxia telangiectasia.
2025-11-25 | MODEL2503190002 | BioModels
Project description:Integrated-systems model of oxidative stress connecting NRF2 and p53 signaling pathways. Additional crosstalk linking oxidative stress to p53 inhibition, p53 to NRF2 through p21, and NRF2 to MDM2 was incorporated in this model. The NRF2 pathway was encoded as first- and second-order rate equations for KEAP1 oxidation and NRF2 stabilization; NRF2-mediated transcription of antioxidant enzymes was modeled as a Hill function. The p53 pathway was reconstructed from a delay differential equation model of p53 signaling in response to DNA damage. To adapt the p53 DNA-damage model to respond to oxidative stress, we used a first-order oxidation reaction of ATM/CHEK2 by intracellular H2O2.
The integrated base model of NRF2–p53 oxidative-stress signaling contains 42 reactions and 22 ordinary differential equations (ODEs).
2021-10-29 | MODEL2110270001 | BioModels
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:Post-transcriptional regulation of cellular mRNA is essential for protein synthesis. Here we describe the importance of mRNA translational repression and mRNA subcellular location for protein expression during B lymphocyte activation and the DNA damage response. Cytoplasmic RNA granules are formed upon cell activation with mitogens, including stress granules that contain the RNA binding protein Tia1. Tia1 binds to a subset of transcripts involved in cell stress, including p53 mRNA, and controls translational silencing and RNA granule localization. DNA damage promotes mRNA relocation and translation in part due to dissociation of Tia1 from its mRNA targets. Upon DNA damage, p53 mRNA is released from stress granules and associates with polyribosomes to increase protein synthesis. Global analysis of cellular mRNA abundance and translation indicates that this is an extended ATM-dependent mechanism to increase protein expression of key modulators of the DNA damage response.
2017-09-13 | GSE93575 | GEO
Project description:Post-transcriptional regulation of cellular mRNA is essential for protein synthesis. Here we describe the importance of mRNA translational repression and mRNA subcellular location for protein expression during B lymphocyte activation and the DNA damage response. Cytoplasmic RNA granules are formed upon cell activation with mitogens, including stress granules that contain the RNA binding protein Tia1. Tia1 binds to a subset of transcripts involved in cell stress, including p53 mRNA, and controls translational silencing and RNA granule localization. DNA damage promotes mRNA relocation and translation in part due to dissociation of Tia1 from its mRNA targets. Upon DNA damage, p53 mRNA is released from stress granules and associates with polyribosomes to increase protein synthesis. Global analysis of cellular mRNA abundance and translation indicates that this is an extended ATM-dependent mechanism to increase protein expression of key modulators of the DNA damage response.
2017-09-13 | GSE93574 | GEO
Project description:Post-transcriptional regulation of cellular mRNA is essential for protein synthesis. Here we describe the importance of mRNA translational repression and mRNA subcellular location for protein expression during B lymphocyte activation and the DNA damage response. Cytoplasmic RNA granules are formed upon cell activation with mitogens, including stress granules that contain the RNA binding protein Tia1. Tia1 binds to a subset of transcripts involved in cell stress, including p53 mRNA, and controls translational silencing and RNA granule localization. DNA damage promotes mRNA relocation and translation in part due to dissociation of Tia1 from its mRNA targets. Upon DNA damage, p53 mRNA is released from stress granules and associates with polyribosomes to increase protein synthesis. Global analysis of cellular mRNA abundance and translation indicates that this is an extended ATM-dependent mechanism to increase protein expression of key modulators of the DNA damage response.
2017-09-13 | GSE93573 | GEO