Study of dynamic transcriptome profiling in DNA damage-induced cellular senescence and transient cell-cycle arrest
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE112068 | GEO | 2018/03/27
REPOSITORIES: GEO
Similar Datasets
Project description:Study of dynamic transcriptome profiling in DNA damage-induced cellular senescence and transient cell-cycle arrest
| PRJNA439216 | ENA
Project description:Senescent cells are a major cause of organismal aging and a key target for anti-aging therapies. Persistent DNA damage signaling is a primary driver of the induction and maintenance of cellular senescence. However, many DNA damaging stimuli that induce senescence, such as irradiation or transient exposure to genotoxic drugs, are transient. The mechanisms underlying persistent damage signaling in senescent cells, and why senescent cells fail to repair damaged DNA, remain unknown. Here, we were able to assess the mechanisms underlying persistence of DNA damage and senescence maintenance by designing a precisely controllable senescence system that does not require potent stressors to induce senescence. We demonstrate that sustained mTORC1 signaling in senescent cells causes gradually accumulating DNA damage and an inflammatory response that maintains cell-cycle arrest. Markedly, activation of E2F transcription, which promotes expression of DNA repair proteins, can reverse accumulated DNA damage. Thus, persistent DNA damage signaling arises in senescent cells by uncoupling of mTORC1 and E2F signaling, whereby prolonged mTORC1 activity causes gradually increasing DNA damage that cannot be sufficiently repaired without induction of protective E2F target genes.
2023-06-01 | GSE153683 | GEO
Project description:Study of dynamic transcriptome profiling in DNA damage-induced cellular senescence and transient cell-cycle arrest
| PRJNA427395 | ENA
Project description:Kollarovic2016 - Cell fate decision at G1-S
transition
This model is described in the article:
To senesce or not to
senesce: how primary human fibroblasts decide their cell fate
after DNA damage.
Kollarovic G, Studencka M, Ivanova
L, Lauenstein C, Heinze K, Lapytsko A, Talemi SR, Figueiredo AS,
Schaber J.
Aging (Albany NY) 2016 Jan;
Abstract:
Excessive DNA damage can induce an irreversible cell cycle
arrest, called senescence, which is generally perceived as an
important tumour-suppressor mechanism. However, it is unclear
how cells decide whether to senesce or not after DNA damage. By
combining experimental data with a parameterized mathematical
model we elucidate this cell fate decision at the G1-S
transition. Our model provides a quantitative and conceptually
new understanding of how human fibroblasts decide whether DNA
damage is beyond repair and senesce. Model and data imply that
the G1-S transition is regulated by a bistable hysteresis
switch with respect to Cdk2 activity, which in turn is
controlled by the Cdk2/p21 ratio rather than cyclin abundance.
We experimentally confirm the resulting predictions that to
induce senescence i) in healthy cells both high initial and
elevated background DNA damage are necessary and sufficient,
and ii) in already damaged cells much lower additional DNA
damage is sufficient. Our study provides a mechanistic
explanation of a) how noise in protein abundances allows cells
to overcome the G1-S arrest even with substantial DNA damage,
potentially leading to neoplasia, and b) how accumulating DNA
damage with age increasingly sensitizes cells for
senescence.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000632.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
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
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000632 | BioModels
Project description:Jaiswal2017 - Cell cycle arrest
This model is described in the article:
ATM/Wip1 activities at
chromatin control Plk1 re-activation to determine G2 checkpoint
duration.
Jaiswal H, Benada J, Müllers E,
Akopyan K, Burdova K, Koolmeister T, Helleday T, Medema RH,
Macurek L, Lindqvist A.
EMBO J. 2017 Jul; 36(14):
2161-2176
Abstract:
After DNA damage, the cell cycle is arrested to avoid
propagation of mutations. Arrest in G2 phase is initiated by
ATM-/ATR-dependent signaling that inhibits mitosis-promoting
kinases such as Plk1. At the same time, Plk1 can counteract
ATR-dependent signaling and is required for eventual resumption
of the cell cycle. However, what determines when Plk1 activity
can resume remains unclear. Here, we use FRET-based reporters
to show that a global spread of ATM activity on chromatin and
phosphorylation of ATM targets including KAP1 control Plk1
re-activation. These phosphorylations are rapidly counteracted
by the chromatin-bound phosphatase Wip1, allowing cell cycle
restart despite persistent ATM activity present at DNA lesions.
Combining experimental data and mathematical modeling, we
propose a model for how the minimal duration of cell cycle
arrest is controlled. Our model shows how cell cycle restart
can occur before completion of DNA repair and suggests a
mechanism for checkpoint adaptation in human cells.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000641.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
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
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000641 | BioModels
Project description:Lentiviral accessory genes enhance replication through diverse mechanisms. HIV-1 accessory protein Vpr modulates the host DNA damage response (DDR) at multiple steps through DNA damage, cell cycle arrest, the degradation of host proteins, and both the activation and repression of DDR signaling. Vpr also alters host and viral transcription; however, the connection between Vpr-mediated DDR modulation and transcriptional activation remains unclear. Here, we determined the cellular consequences of Vpr-induced DNA damage using Vpr mutants that allow us to separate the ability of Vpr to induce DNA damage from cell cycle arrest and other DDR phenotypes including host protein degradation and repression of DDR. RNA-sequencing of cells expressing Vpr or Vpr mutants identified that Vpr alters cellular transcription through mechanisms both dependent and independent of cell cycle arrest. In tissue-cultured U2OS cells and primary human monocyte-derived macrophages (MDMs), Vpr-induced DNA damage activates the ATM-NEMO pathway and alters cellular transcription via NF-κB/RelA signaling. HIV-1 infection of primary MDMs validated Vpr-dependent NF-κB transcriptional activation during infection. Both virion delivered and de novo expressed Vpr induced DNA damage and activated ATM-NEMO dependent NF-κB transcription, suggesting that engagement of the DDR and transcriptional reprogramming can occur during early and late stages of viral replication. Together, our data identifies a mechanism by which Vpr activates NF-κB through DNA damage and the ATM-NEMO pathway, which occur independent of cell cycle arrest. We propose this is essential to overcoming restrictive environments, such as in macrophages, to enhance viral transcription and replication.
2024-08-23 | GSE253779 | GEO
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:Glioblastoma (GBM) is the most aggressive brain tumor and resistant to current available therapeutics, such as radiation. To improve the clinical efficacy, it is important to understand the cellular mechanisms underlying tumor responses to radiation. Here, we investigated long-term cellular responses of human GBM cells to ionizing radiation. Comparing to the initial response within 12 hours, gene expression modulation at 7 days after radiation is markedly different. While genes related to cell cycle arrest and DNA damage responses are mostly modulated at the initial stage; immune-related genes are specifically affected as the long-term effect. This later response is associated with increased cellular senescence and inhibition of transcriptional coactivator with PDZ-binding motif (TAZ). Mechanistically, TAZ inhibition does not depend on the canonical Hippo pathway, but relies on enhanced degradation mediated by the β-catenin destruction complex in the Wnt pathway. We further showed that depletion of TAZ by RNAi promotes radiation-induced senescence and growth arrest. Pharmacological activation of the β-catenin destruction complex is able to promote radiation-induced TAZ inhibition and growth arrest in these tumor cells. The correlation between senescence and reduced expression of YAP as well as β-catenin also occurs in human gliomas treated by radiation. Collectively, these findings suggested that inhibition of TAZ is involved in radiation-induced senescence and might benefit GBM radiotherapy.
2019-02-25 | GSE121422 | GEO
Project description:DallePazze2014 - Cellular senescene-induced
mitochondrial dysfunction
This model is described in the article:
Dynamic modelling of
pathways to cellular senescence reveals strategies for targeted
interventions.
Dalle Pezze P, Nelson G, Otten EG,
Korolchuk VI, Kirkwood TB, von Zglinicki T, Shanley DP.
PLoS Comput. Biol. 2014 Aug; 10(8):
e1003728
Abstract:
Cellular senescence, a state of irreversible cell cycle
arrest, is thought to help protect an organism from cancer, yet
also contributes to ageing. The changes which occur in
senescence are controlled by networks of multiple signalling
and feedback pathways at the cellular level, and the interplay
between these is difficult to predict and understand. To
unravel the intrinsic challenges of understanding such a highly
networked system, we have taken a systems biology approach to
cellular senescence. We report a detailed analysis of
senescence signalling via DNA damage, insulin-TOR, FoxO3a
transcription factors, oxidative stress response, mitochondrial
regulation and mitophagy. We show in silico and in vitro that
inhibition of reactive oxygen species can prevent loss of
mitochondrial membrane potential, whilst inhibition of mTOR
shows a partial rescue of mitochondrial mass changes during
establishment of senescence. Dual inhibition of ROS and mTOR in
vitro confirmed computational model predictions that it was
possible to further reduce senescence-induced mitochondrial
dysfunction and DNA double-strand breaks. However, these
interventions were unable to abrogate the senescence-induced
mitochondrial dysfunction completely, and we identified
decreased mitochondrial fission as the potential driving force
for increased mitochondrial mass via prevention of mitophagy.
Dynamic sensitivity analysis of the model showed the network
stabilised at a new late state of cellular senescence. This was
characterised by poor network sensitivity, high signalling
noise, low cellular energy, high inflammation and permanent
cell cycle arrest suggesting an unsatisfactory outcome for
treatments aiming to delay or reverse cellular senescence at
late time points. Combinatorial targeted interventions are
therefore possible for intervening in the cellular pathway to
senescence, but in the cases identified here, are only capable
of delaying senescence onset.
This model is hosted on
BioModels Database
and identified by:
BIOMD0000000582.
To cite BioModels Database, please use:
BioModels Database:
An enhanced, curated and annotated resource for published
quantitative kinetic models.
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
CC0
Public Domain Dedication for more information.
2024-09-02 | BIOMD0000000582 | BioModels
Project description:Oncogene-induced senescence is an anti-proliferative stress response program that acts as a fail-safe mechanism to limit oncogenic transformation and is regulated by the retinoblastoma protein (RB) and p53 tumor suppressor pathways. We identify the atypical E2F family member E2F7 as the only E2F transcription factor potently upregulated during oncogene-induced senescence, a setting where it acts in response to p53 as a direct transcriptional target. Once induced, E2F7 binds and represses a series of E2F target genes and cooperates with RB to efficiently promote cell cycle arrest and limit oncogenic transformation. Disruption of RB triggers a further increase in E2F7, which induces a second cell cycle checkpoint that prevents unconstrained cell division despite aberrant DNA replication. Mechanistically, E2F7 compensates for the loss of RB in repressing mitotic E2F target genes. To understand the contribution of different genes, especially E2F7 to the expression profile of senescent cells, we infected human IMR90 cells with Ras and different hairpins. The infected population was selected using first with 2 ug/ml puromycin (Sigma) for 2 days, then 100 ug/ml hygromycin B (Roche) for 3 days. RNA was isolated 7 days after the puromycin selection and hybridized to Affymetrix microarrays. We tried to understand the effect of E2F7 in the transcription profile of senescent cells.
2012-08-25 | E-GEOD-40349 | biostudies-arrayexpress