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Accumulating DNA damage and insufficient DNA repair in senescent cells underlie persistent DNA damage signaling

ABSTRACT: Accumulating DNA damage and insufficient DNA repair in senescent cells underlie persistent DNA damage signaling

PROVIDER: PRJNA643685 | ENA |

REPOSITORIES: ENA

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Accumulating DNA damage and insufficient DNA repair in senescent cells underlie persistent DNA damage signaling

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

A metabolic map of the DNA damage response identifies PRDX1 in nuclear ROS scavenging and aspartate synthesis

Project description:Targetted metabolomics in U2OS PRDX1 WT and PRDX1-/- While cellular metabolism impacts the DNA damage response, a systematic understanding of the metabolic requirements that are crucial for DNA damage repair has yet to be achieved. Here, we investigate the metabolic enzymes and processes that are essential when cells are exposed to DNA damage. By integrating functional genomics with chromatin proteomics and metabolomics, we provide a detailed description of the interplay between cellular metabolism and the DNA damage response. Subsequent analysis identified Peroxiredoxin 1, PRDX1, as fundamental for DNA damage repair. During the DNA damage response, PRDX1 translocates to the nucleus where it is required to reduce DNA damage-induced nuclear reactive oxygen species levels. Moreover, PRDX1 controls aspartate availability, which is required for the DNA damage repair-induced upregulation of de novo nucleotide synthesis. Loss of PRDX1 leads to an impairment in the clearance of γΗ2ΑΧ nuclear foci, accumulation of replicative stress and cell proliferation defects, thus revealing a crucial role for PRDX1 as a DNA damage surveillance factor.

2022-07-19 | ST002234 | MetabolomicsWorkbench

Accumulating Oxidative DNA Damage in Reconstituting T-cells is Associated with Disease Relapse and Inferior Survival Following Allo-SCT

Project description:Accumulating Oxidative DNA Damage in Reconstituting T-cells is Associated with Disease Relapse and Inferior Survival Following Allo-SCT

| PRJNA842332 | ENA

Iwamoto2010 - Cell cycle reponse to DNA damage

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

RasV12 blocks DNA synthesis and DNA damage response

Project description:RasV12 blocks DNA synthesis and DNA damage response

| PRJNA524372 | ENA

Accumulating Oxidative DNA Damage in Reconstituting T-cells is Associated with Disease Relapse and Inferior Survival Following Allo-SCT [RNAseq in vivo]

Project description:Oxidative T-cell DNA damage impacts GVL

2024-05-01 | GSE204782 | GEO

Accumulating Oxidative DNA Damage in Reconstituting T-cells is Associated with Disease Relapse and Inferior Survival Following Allo-SCT [RNAseq in vitro]

Project description:Oxidative T-cell DNA damage impacts GVL

2024-05-01 | GSE204781 | GEO

Aguda1999 - G2 DNA damage checkpoint

Project description:Baltazar D. Aguda. A quantitative analysis of the kinetics of the G(2) DNA damage checkpoint system. Proceedings of the National Academy of Sciences 96, 20 (1999). A detailed model of the G(2) DNA damage checkpoint (G2DDC) system is presented that includes complex regulatory networks of the mitotic kinase Cdc2, phosphatase Cdc25, Wee1 kinase, and damage signal transduction pathways involving Chk1 and p53. Assumptions on the kinetic equations of the G2DDC are made, and computer simulations are carried out to demonstrate how the various subsystems operate to delay or arrest cell cycle progression. The detailed model could be used to explain various experiments relevant to G2DDC reported recently, including the nuclear export of 14-3-3-bound Cdc25, the down-regulation of cyclin B1 expression by p53, the effect of Chk1 and p53 on Cdc25 levels, and Wee1 degradation. It also is shown that, under certain conditions, p53 is necessary to sustain a G(2) arrest.

2024-09-02 | BIOMD0000000704 | BioModels

Accumulating mitochondrial DNA mutations drive premature hematopoietic aging phenotypes molecularly distinct from physiologic stem cell aging

Project description:Somatic stem cells mediate tissue maintenance for the lifetime of an organism. Despite the well-established longevity that is a prerequisite for such function, accumulating data argue for compromised stem cell function with age. Identifying the mechanisms underlying age-dependent stem cell dysfunction is therefore key to understand the aging process. Using a model that carries a proofreading defective mitochondrial DNA polymerase, we demonstrate hematopoietic defects reminiscent of premature HSC aging including anemia, lymphopenia and myeloid lineage skewing. However, in contrast to physiologic stem cell aging, rapidly accumulating mitochondrial DNA mutations displayed little involvement of the hematopoietic stem cell pool but rather with distinct differentiation blocks and/or disappearance of downstream progenitors. Hematopoietic stem cells (HSC) has been sorted out from midaged wildtype and mutator mice and compared with stem cells sorted from young and and old wt mice

2011-05-06 | E-GEOD-27686 | biostudies-arrayexpress

LncRNA DINO guides DNA damage signaling

Project description:LncRNA DINO guides DNA damage signaling

| PRJNA307252 | ENA