Coordination of miR-192 and miR-22 in p53-Mediated Cell Fate Decision

p53-targeted microRNAs (miRNAs) markedly affect cellular response to DNA damage. These miRNAs may contribute to either cell cycle arrest or apoptosis induction. However, how these miRNAs coordinate to modulate the decision between cell survival and death remains less understood. Here, we developed an integrated model of p53 signaling network to investigate how p53-targeted miR-192 and miR-22 modulate cellular outcome in response to DNA damage. By numerical simulations, we found that p53 is activated progressively depending on the extent of DNA damage. Upon moderate damage, p53 rises to medium levels and induces miR-192 to promote its own activation, facilitating p21 induction and cell cycle arrest. Upon severe damage, p53 reaches high levels and is fully activated due to phosphatase and tensin homolog (PTEN) induction. As a result, it transactivates miR-22 to repress p21 expression and activate E2F1, resulting in apoptosis. Therefore, miR-192 promotes primary activation of p53, while miR-22 promotes apoptosis by downregulating p21. This work may advance the understanding of the mechanism for cell fate decision between life and death by p53-inducible miRNAs.

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Coordination between Cell Cycle Progression and Cell Fate Decision by the p53 and E2F1 Pathways in Response to DNA Damage

Journal of Biological Chemistry ◽

10.1074/jbc.m110.134650 ◽

2010 ◽

Vol 285 (41) ◽

pp. 31571-31580 ◽

Cited By ~ 36

Author(s):

Xiao-Peng Zhang ◽

Feng Liu ◽

Wei Wang

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Fate ◽

Cell Cycle Progression ◽

Cell Fate Decision ◽

Cycle Progression ◽

Fate Decision

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The Histone Code of Senescence

Cells ◽

10.3390/cells9020466 ◽

2020 ◽

Vol 9 (2) ◽

pp. 466 ◽

Cited By ~ 6

Author(s):

Harikrishnareddy Paluvai ◽

Eros Di Giorgio ◽

Claudio Brancolini

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Cellular Response ◽

Premature Aging ◽

Physiological Processes ◽

Cycle Arrest ◽

Damage Response ◽

Permanent Cell ◽

Second Wave

Senescence is the end point of a complex cellular response that proceeds through a set of highly regulated steps. Initially, the permanent cell-cycle arrest that characterizes senescence is a pro-survival response to irreparable DNA damage. The maintenance of this prolonged condition requires the adaptation of the cells to an unfavorable, demanding and stressful microenvironment. This adaptation is orchestrated through a deep epigenetic resetting. A first wave of epigenetic changes builds a dam on irreparable DNA damage and sustains the pro-survival response and the cell-cycle arrest. Later on, a second wave of epigenetic modifications allows the genomic reorganization to sustain the transcription of pro-inflammatory genes. The balanced epigenetic dynamism of senescent cells influences physiological processes, such as differentiation, embryogenesis and aging, while its alteration leads to cancer, neurodegeneration and premature aging. Here we provide an overview of the most relevant histone modifications, which characterize senescence, aging and the activation of a prolonged DNA damage response.

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The role of FOXO3 in DNA damage response in thyrocytes

Endocrine Related Cancer ◽

10.1530/erc-11-0138 ◽

2011 ◽

Vol 18 (5) ◽

pp. 555-564 ◽

Cited By ~ 6

Author(s):

Antje Klagge ◽

Carl Weidinger ◽

Kerstin Krause ◽

Beate Jessnitzer ◽

Monika Gutknecht ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Cellular Response ◽

Wild Type ◽

Cycle Arrest ◽

Damage Repair ◽

Cell Clones ◽

Human Wild Type

Members of the forkhead box-O (FOXO) transcription factors family play an important role in stress defence. FOXO3 deregulation has recently been identified as a hallmark of thyroid carcinogenesis. In this study, we explore the role of FOXO3 in defence of oxidative stress in normal thyrocytes. Stable rat thyroid cell lines were generated expressing either the human wild-type FOXO3, a constitutively activating FOXO3 mutant, or the empty control vector. Cell clones were characterised for proliferation, function and morphology. Hydrogen peroxide and UV irradiation were used to induce oxidative stress. Changes in FOXO3 activity, induction of cell cycle arrest or apoptosis and kinetics of DNA damage repair were analysed. Upregulation of FOXO3 in thyrocytes resulted in decreased proliferation and changes in morphology, but did not affect differentiation. Hydrogen peroxide stimulated the expression of the FOXO3 target genes growth arrest and DNA damage-inducible protein 45 α (Gadd45α) and Bcl-2 interacting mediator of cell death (BIM) and induced programmed cell death in cells with overexpression of the human wild-type FOXO3. In contrast, UV irradiation resulted in a distinct cellular response with activation of FOXO3-c-Jun-N-terminal kinase-Gadd45α signalling and induction of cell cycle arrest at the G2-M-checkpoint. This was accompanied by FOXO3-induced DNA damage repair as evidenced by lower DNA breaks over time in a comet assay in FOXO3 cell clones compared with control cells. In conclusion, FOXO3 is a pivotal relay in the coordination of the cellular response to genotoxic stress in the thyroid. Depending on the stimulus, FOXO3 induces either cell cycle arrest or apoptosis. Conversely, FOXO3 inactivation in thyroid cancers is consistent with genomic instability and loss of cell cycle control.

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H2AX Is Required for Cell Cycle Arrest via the p53/p21 Pathway

Molecular and Cellular Biology ◽

10.1128/mcb.01830-08 ◽

2009 ◽

Vol 29 (10) ◽

pp. 2828-2840 ◽

Cited By ~ 87

Author(s):

Michalis Fragkos ◽

Jaana Jurvansuu ◽

Peter Beard

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Cellular Response ◽

Replication Fork ◽

Mitotic Catastrophe ◽

Adeno Associated Virus ◽

Cycle Arrest ◽

And Diffusion

ABSTRACT Phosphorylation of H2AX (γH2AX) is an early sign of DNA damage induced by replication stalling. However, the role of H2AX in the repair of this type of DNA damage is still unclear. In this study, we used an inactivated adeno-associated virus (AAV) to induce a stalled replication fork signal and investigate the function of γH2AX. The cellular response to AAV provides a unique model to study γH2AX function, because the infection causes pannuclear H2AX phosphorylation without any signs of damage to the host genome. We found that pannuclear γH2AX formation is a result of ATR overactivation and diffusion but is independent of ATM. The inhibition of H2AX with RNA interference or the use of H2AX-deficient cells showed that γH2AX is dispensable for the formation and maintenance of DNA repair foci induced by stalled replication. However, in the absence of H2AX, the AAV-containing cells showed proteosome-dependent degradation of p21, followed by caspase-dependent mitotic catastrophe. In contrast, H2AX-proficient cells as well as H2AX-complemented H2AX−/− cells reacted by increasing p21 levels and arresting the cell cycle. The results establish a new role for H2AX in the p53/p21 pathway and indicate that H2AX is required for p21-induced cell cycle arrest after replication stalling.

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NRF2 preserves genomic integrity by facilitating ATR activation and G2 cell cycle arrest

Nucleic Acids Research ◽

10.1093/nar/gkaa631 ◽

2020 ◽

Vol 48 (16) ◽

pp. 9109-9123 ◽

Cited By ~ 2

Author(s):

Xiaohui Sun ◽

Yan Wang ◽

Kaihua Ji ◽

Yang Liu ◽

Yangyang Kong ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Cellular Response ◽

Genome Stability ◽

Related Factor ◽

Dna Double Strand Breaks ◽

Ros Scavenging ◽

Cycle Arrest ◽

G2 Cell Cycle Arrest

Abstract Nuclear factor erythroid 2-related factor 2 (NRF2) is a well-characterized transcription factor that protects cells against oxidative and electrophilic stresses. Emerging evidence has suggested that NRF2 protects cells against DNA damage by mechanisms other than antioxidation, yet the mechanism remains poorly understood. Here, we demonstrate that knockout of NRF2 in cells results in hypersensitivity to ionizing radiation (IR) in the presence or absence of reactive oxygen species (ROS). Under ROS scavenging conditions, induction of DNA double-strand breaks (DSBs) increases the NRF2 protein level and recruits NRF2 to DNA damage sites where it interacts with ATR, resulting in activation of the ATR–CHK1–CDC2 signaling pathway. In turn, this leads to G2 cell cycle arrest and the promotion of homologous recombination repair of DSBs, thereby preserving genome stability. The inhibition of NRF2 by brusatol increased the radiosensitivity of tumor cells in xenografts by perturbing ATR and CHK1 activation. Collectively, our results reveal a novel function of NRF2 as an ATR activator in the regulation of the cellular response to DSBs. This shift in perspective should help furnish a more complete understanding of the function of NRF2 and the DNA damage response.

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Design, Synthesis and Pharmacological Evaluation of Three Novel Dehydroabietyl Piperazine Dithiocarbamate Ruthenium (II) Polypyridyl Complexes as Potential Antitumor Agents: DNA Damage, Cell Cycle Arrest and Apoptosis Induction

Molecules ◽

10.3390/molecules26051453 ◽

2021 ◽

Vol 26 (5) ◽

pp. 1453

Author(s):

Haoran Wang ◽

Jianhua Wei ◽

Hong Jiang ◽

Ye Zhang ◽

Caina Jiang ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Antitumor Agents ◽

Mechanistic Study ◽

Ros Generation ◽

Polypyridyl Complexes ◽

Expression Levels ◽

Cycle Arrest ◽

Study Results

The use of cisplatin is severely limited by its toxic side-effects, which has spurred chemists to employ different strategies in the development of new metal-based anticancer agents. Here, three novel dehydroabietyl piperazine dithiocarbamate ruthenium (II) polypyridyl complexes (6a–6c) were synthesized as antitumor agents. Compounds 6a and 6c exhibited better in vitro antiproliferative activity against seven tumor cell lines than cisplatin, they displayed no evident resistance in the cisplatin-resistant cell line A549/DPP. Importantly, 6a effectively inhibited tumor growth in the T-24 xenograft mouse model in comparison with cisplatin. Gel electrophoresis assay indicated that DNA was the potential targets of 6a and 6c, and the upregulation of p-H2AX confirmed this result. Cell cycle arrest studies demonstrated that 6a and 6c arrested the cell cycle at G1 phase, accompanied by the upregulation of the expression levels of the antioncogene p27 and the down-regulation of the expression levels of cyclin E. In addition, 6a and 6c caused the apoptosis of tumor cells along with the upregulation of the expression of Bax, caspase-9, cytochrome c, intracellular Ca2+ release, reactive oxygen species (ROS) generation and the downregulation of Bcl-2. These mechanistic study results suggested that 6a and 6c exerted their antitumor activity by inducing DNA damage, and consequently causing G1 stage arrest and the induction of apoptosis.

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ERK activation mediates cell cycle arrest and apoptosis after DNA damage independently of p53.

Journal of Biological Chemistry ◽

10.1016/s0021-9258(20)84970-9 ◽

2002 ◽

Vol 277 (23) ◽

pp. 21110 ◽

Cited By ~ 1

Author(s):

Damu Tang ◽

Dongcheng Wu ◽

Atsushi Hirao ◽

Jill M. Lahti ◽

Lieqi Liu ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Erk Activation ◽

Cycle Arrest

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P28-10 Cisplatin induces DNA damage associated with cell cycle arrest and apoptosis in PC9 cells

Annals of Oncology ◽

10.1016/j.annonc.2021.05.736 ◽

2021 ◽

Vol 32 ◽

pp. S346

Author(s):

Md Mohiuddin ◽

Hideharu Kimura ◽

Takashi Sone ◽

Hiroki Matsuoka ◽

Keigo Saeki ◽

...

Keyword(s):

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Cycle Arrest

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Inflammation, epigenetics, and metabolism converge to cell senescence and ageing: the regulation and intervention

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00646-9 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Xudong Zhu ◽

Zhiyang Chen ◽

Weiyan Shen ◽

Gang Huang ◽

John M. Sedivy ◽

...

Keyword(s):

Cell Fate ◽

Cellular Response ◽

State Of The Art ◽

Cell Senescence ◽

Therapeutic Interventions ◽

Cell Fate Decision ◽

The Past ◽

Fate Decision ◽

The Individual ◽

Remarkable Progress

AbstractRemarkable progress in ageing research has been achieved over the past decades. General perceptions and experimental evidence pinpoint that the decline of physical function often initiates by cell senescence and organ ageing. Epigenetic dynamics and immunometabolic reprogramming link to the alterations of cellular response to intrinsic and extrinsic stimuli, representing current hotspots as they not only (re-)shape the individual cell identity, but also involve in cell fate decision. This review focuses on the present findings and emerging concepts in epigenetic, inflammatory, and metabolic regulations and the consequences of the ageing process. Potential therapeutic interventions targeting cell senescence and regulatory mechanisms, using state-of-the-art techniques are also discussed.

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