DNA damage response in single RPE-FUCCI cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE146759 | GEO | 2020/12/01
REPOSITORIES: GEO
Similar Datasets
Project description:E2F transcription factors are known to be important for timely activation of G1/S and G2/M genes required for cell cycle progression, but transcriptional mechanisms for deactivation of cell cycle regulated genes are unknown. Here, we show that E2F7 is highly expressed during mid to late S-phase, occupies promoters of G1/S regulated genes and represses its transcription. ChIP-seq analysis revealed that E2F7 binds preferentially to genomic sites containing the TTCCCGCC motif, which closely resemble the E2F consensus site. We identified 89 target genes that carry E2F7 binding sites close to the transcriptional start site and that are directly repressed by short term induction of E2F7. Most of these target genes are known to be activated by E2Fs and are involved in DNA replication, metabolism and DNA repair. Importantly, induction of E2F7 during G0-G1/S resulted in S-phase arrest and DNA damage, whereas expression of E2F7 during G2/M failed to disturb cell cycle progression. These findings provide strong evidence that E2F7 controls directly the downswing of oscillating G1/S genes during S-phase progression.
2012-01-04 | GSE32673 | GEO
Project description:E2F transcription factors are known to be important for timely activation of G1/S and G2/M genes required for cell cycle progression, but transcriptional mechanisms for deactivation of cell cycle-regulated genes are unknown. Here, we show that E2F7 is highly expressed during mid to late S-phase, occupies promoters of G1/S-regulated genes and represses their transcription. ChIP-seq analysis revealed that E2F7 binds preferentially to genomic sites containing the TTCCCGCC motif, which closely resemble the E2F consensus site. We identified 89 target genes that carry E2F7 binding sites close to the transcriptional start site and that are directly repressed by short term induction of E2F7. Most of these target genes are known to be activated by E2Fs and are involved in DNA replication, metabolism and DNA repair. Importantly, induction of E2F7 during G0-G1/S resulted in S-phase arrest and DNA damage, whereas expression of E2F7 during G2/M failed to disturb cell cycle progression. These findings provide strong evidence that E2F7 directly controls the downswing of oscillating G1/S genes during S-phase progression.
2012-05-01 | GSE33448 | GEO
Project description:Not many models of mammalian cell cycle system exist due to its complexity. Some models are too complex and hard to understand, while some others are too simple and not comprehensive enough. Moreover, some essential aspects, such as the response of G1-S and G2-M checkpoints to DNA damage as well as the growth factor signalling, have not been investigated from a systems point of view in current mammalian cell cycle models. To address these issues, we bring a holistic perspective to cell cycle by mathematically modelling it as a complex system consisting of important sub-systems that interact with each other. This retains the functionality of the system and provides a clearer interpretation to the processes within it while reducing the complexity in comprehending these processes. To achieve this, we first update a published ODE mathematical model of cell cycle with current knowledge. Then the part of the mathematical model relevant to each sub-system is shown separately in conjunction with a diagram of the sub-system as part of this representation. The model sub-systems are Growth Factor, DNA damage, G1-S, and G2-M checkpoint signalling. To further simplify the model and better explore the function of sub-systems, they are further divided into modules. Here we also add important new modules of: chk-related rapid cell cycle arrest, p53 modules expanded to seamlessly integrate with the rapid arrest module, Tyrosine phosphatase modules that activate Cyc_Cdk complexes and play a crucial role in rapid and delay arrest at both G1-S and G2-M, Tyrosine Kinase module that is important for inactivating nuclear transport of CycB_cdk1 through Wee1 to resist M phase entry, Plk1-Related module that is crucial in activating Tyrosine phosphatases and inactivating Tyrosine kinase, and APC-Related module to show steps in CycB degradation. This multi-level systems approach incorporating all known aspects of cell cycle allowed us to (i) study, through dynamic simulation of an ODE model, comprehensive details of cell cycle dynamics under normal and DNA damage conditions revealing the role and value of the added new modules and elements, (ii) assess, through a global sensitivity analysis, the most influential sub-systems, modules and parameters on system response, such as G1-S and G2-M transitions, and (iii) probe deeply into the relationship between DNA damage and cell cycle progression and test the biological evidence that G1-S is relatively inefficient in arresting damaged cells compared to G2-M checkpoint. To perform sensitivity analysis, Self-Organizing Map with Correlation Coefficient Analysis (SOMCCA) is developed which shows that Growth Factor and G1-S Checkpoint sub-systems and 13 parameters in the modules within them are crucial for G1-S and G2-M transitions. To study the relative efficiency of DNA damage checkpoints, a Checkpoint Efficiency Evaluator (CEE) is developed based on perturbation studies and statistical Type II error. Accordingly, cell cycle is about 96% efficient in arresting damaged cells with G2-M checkpoint being more efficient than G1-S. Further, both checkpoint systems are near perfect (98.6%) in passing healthy cells. Thus this study has shown the efficacy of the proposed systems approach to gain a better understanding of different aspects of mammalian cell cycle system separately and as an integrated system that will also be useful in investigating targeted therapy in future cancer treatments.
2018-12-13 | MODEL1812130001 | BioModels
Project description:E2F transcription factors are known to be important for timely activation of G1/S and G2/M genes required for cell cycle progression, but transcriptional mechanisms for deactivation of cell cycle regulated genes are unknown. Here, we show that E2F7 is highly expressed during mid to late S-phase, occupies promoters of G1/S regulated genes and represses its transcription. ChIP-seq analysis revealed that E2F7 binds preferentially to genomic sites containing the TTCCCGCC motif, which closely resemble the E2F consensus site. We identified 89 target genes that carry E2F7 binding sites close to the transcriptional start site and that are directly repressed by short term induction of E2F7. Most of these target genes are known to be activated by E2Fs and are involved in DNA replication, metabolism and DNA repair. Importantly, induction of E2F7 during G0-G1/S resulted in S-phase arrest and DNA damage, whereas expression of E2F7 during G2/M failed to disturb cell cycle progression. These findings provide strong evidence that E2F7 controls directly the downswing of oscillating G1/S genes during S-phase progression. 2 samples: E2F7 ChIP-seq and input control, E2F7 ChIP-seq sample was sequenced in 2 independent runs and data were combined for the analysis
2012-01-04 | E-GEOD-32673 | biostudies-arrayexpress
Project description:E2F transcription factors are known to be important for timely activation of G1/S and G2/M genes required for cell cycle progression, but transcriptional mechanisms for deactivation of cell cycle-regulated genes are unknown. Here, we show that E2F7 is highly expressed during mid to late S-phase, occupies promoters of G1/S-regulated genes and represses their transcription. ChIP-seq analysis revealed that E2F7 binds preferentially to genomic sites containing the TTCCCGCC motif, which closely resemble the E2F consensus site. We identified 89 target genes that carry E2F7 binding sites close to the transcriptional start site and that are directly repressed by short term induction of E2F7. Most of these target genes are known to be activated by E2Fs and are involved in DNA replication, metabolism and DNA repair. Importantly, induction of E2F7 during G0-G1/S resulted in S-phase arrest and DNA damage, whereas expression of E2F7 during G2/M failed to disturb cell cycle progression. These findings provide strong evidence that E2F7 directly controls the downswing of oscillating G1/S genes during S-phase progression. Overexpression of E2F7 was studied in a doxycyclin-inducable system. Four cellcultures were treated with and without doxycyclin and RNA was isolated to run direct comparisons on a 2-channel human expression microarray.
2012-04-30 | E-GEOD-33448 | biostudies-arrayexpress
Project description:Barr2017 - Dynamics of p21 in hTert-RPE1
cells
This deteministic model reveals that a
bistable switch created by Cdt2, promotes irreversible S-phase
entry by keeping p21 levels low, prevents premature S-phase exit
upon DNA damage
This model is described in the article:
DNA damage during S-phase
mediates the proliferation-quiescence decision in the
subsequent G1 via p21 expression.
Barr AR, Cooper S, Heldt FS, Butera
F, Stoy H, Mansfeld J, Novák B, Bakal C.
Nat Commun 2017 Mar; 8: 14728
Abstract:
Following DNA damage caused by exogenous sources, such as
ionizing radiation, the tumour suppressor p53 mediates cell
cycle arrest via expression of the CDK inhibitor, p21. However,
the role of p21 in maintaining genomic stability in the absence
of exogenous DNA-damaging agents is unclear. Here, using live
single-cell measurements of p21 protein in proliferating
cultures, we show that naturally occurring DNA damage incurred
over S-phase causes p53-dependent accumulation of p21 during
mother G2- and daughter G1-phases. High p21 levels mediate G1
arrest via CDK inhibition, yet lower levels have no impact on
G1 progression, and the ubiquitin ligases CRL4Cdt2 and SCFSkp2
couple to degrade p21 prior to the G1/S transition.
Mathematical modelling reveals that a bistable switch, created
by CRL4Cdt2, promotes irreversible S-phase entry by keeping p21
levels low, preventing premature S-phase exit upon DNA damage.
Thus, we characterize how p21 regulates the
proliferation-quiescence decision to maintain genomic
stability.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000660.
To cite BioModels Database, please use:
Chelliah V et al. BioModels: ten-year
anniversary. Nucl. Acids Res. 2015, 43(Database
issue):D542-8.
To the extent possible under law, all copyright and related or
neighbouring rights to this encoded model have been dedicated to
the public domain worldwide. Please refer to
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2024-09-02 | BIOMD0000000660 | BioModels
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2024-09-02 | BIOMD0000000954 | BioModels
Project description:CDK4/6 inhibitors arrest the cell cycle in G1-phase. They are licenced to treat breast cancer and are also undergoing clinical trials against a range of other tumour types. To facilitate these efforts, it is important to understand why a temporary cell cycle arrest in G1 causes long-lasting effects on tumour growth. Here we demonstrate that a prolonged G1-arrest following CDK4/6 inhibition downregulates replisome components and impairs origin licencing. This causes a failure in DNA replication after release from that arrest, resulting in a p53-dependent withdrawal from the cell cycle. If p53 is absent, then cells bypass the G2-checkpoint and undergo a catastrophic mitosis resulting in excessive DNA damage. These data therefore link CDK4/6 inhibition to genotoxic stress; a phenotype that is shared by most other broad-spectrum anti-cancer drugs. This provides a rationale to predict responsive tumour types and effective combination therapies, as demonstrated by the fact that chemotherapeutics that cause replication stress also induce sensitivity to CDK4/6 inhibition.
2021-12-20 | PXD023435 | Pride
Project description:Bela Novak & John J. Tyson. Mitotic kinase oscillation governs the latching of cell cycle switches. Current Biology 32, 12 (2022).
In 1996, Kim Nasmyth1 proposed that the eukaryotic cell cycle is an alternating sequence of transitions from G1 to S-G2-M and back again. These two phases correlate to high activity of cyclin-dependent kinases (CDKs) that trigger S-G2-M events and CDK antagonists that stabilize G1 phase. We associated these “alternative phases” with the coexistence of two stable steady states of the biochemical reactions among CDKs and their antagonists. Transitions between these steady states (G1-to-S and M-to-G1) are driven by “helper” proteins. The fact that the transitions are irreversible is guaranteed by a “latching” property of the molecular switches, as we have argued in previous publications. Here, we show that if the latch is broken, then the biochemical reactions can swing back-and-forth across the transitions; either G1-S-G1-S … (periodic DNA replication without mitosis or cell division) or M-(G1)-M-(G1) … (periodic Cdc14 release, without fully exiting mitosis). Using mathematical modeling of the molecular control circuit in budding yeast, we provide a fresh account of aberrant cell cycles in mutant strains: endoreplication in the clb1-5Δ strain and periodic release and resequestration of Cdc14 (an “exit” phosphatase) in the CLB2kdΔ strain.7,8 In our opinion, these “endocycles” are not autonomous oscillatory modules that must be entrained by the CDK oscillator but rather inadvertent and deleterious oscillations that are normally suppressed by the CDK latching-gate mechanism.
2024-09-02 | BIOMD0000001058 | BioModels
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