scholarly journals Exosomes maintain cellular homeostasis by excreting harmful DNA from cells

2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Akiko Takahashi ◽  
Ryo Okada ◽  
Koji Nagao ◽  
Yuka Kawamata ◽  
Aki Hanyu ◽  
...  
Keyword(s):  
Dna Damage Response ◽  
Nuclear Dna ◽  
Innate Immune ◽  
Oxygen Species ◽  
Chromosomal Dna ◽  
Cellular Homeostasis ◽  
Cycle Arrest ◽  
Cytoplasmic Dna ◽  
Damage Response ◽  
Normal Human

Abstract Emerging evidence is revealing that exosomes contribute to many aspects of physiology and disease through intercellular communication. However, the biological roles of exosome secretion in exosome-secreting cells have remained largely unexplored. Here we show that exosome secretion plays a crucial role in maintaining cellular homeostasis in exosome-secreting cells. The inhibition of exosome secretion results in the accumulation of nuclear DNA in the cytoplasm, thereby causing the activation of cytoplasmic DNA sensing machinery. This event provokes the innate immune response, leading to reactive oxygen species (ROS)-dependent DNA damage response and thus induce senescence-like cell-cycle arrest or apoptosis in normal human cells. These results, in conjunction with observations that exosomes contain various lengths of chromosomal DNA fragments, indicate that exosome secretion maintains cellular homeostasis by removing harmful cytoplasmic DNA from cells. Together, these findings enhance our understanding of exosome biology, and provide valuable new insights into the control of cellular homeostasis.

scholarly journals Interplay between Mdm2 and HIPK2 in the DNA damage response

2014 ◽  
Vol 11 (96) ◽  
pp. 20140319 ◽  
Author(s):  
Xiao-Peng Zhang ◽  
Feng Liu ◽  
Wei Wang
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Negative Regulator ◽  
Critical Event ◽  
Apoptosis Induction ◽  
Nuclear Entry ◽  
Induce Cell Cycle Arrest ◽  
Interacting Protein ◽  
Cycle Arrest ◽  
Damage Response

The tumour suppressor p53 is activated to induce cell-cycle arrest or apoptosis in the DNA damage response (DDR). p53 phosphorylation at Ser46 by HIPK2 (homeodomain-interacting protein kinase 2) is a critical event in apoptosis induction. Interestingly, HIPK2 is degraded by Mdm2 (a negative regulator of p53), whereas Mdm2 is downregulated by HIPK2 through several mechanisms. Here, we develop a four-module network model for the p53 pathway to clarify the role of interplay between Mdm2 and HIPK2 in the DDR evoked by ultraviolet radiation. By numerical simulations, we reveal that Mdm2-dependent HIPK2 degradation promotes cell survival after mild DNA damage and that inhibition of HIPK2 degradation is sufficient to trigger apoptosis. In response to severe damage, p53 phosphorylation at Ser46 is promoted by the accumulation of HIPK2 due to downregulation of nuclear Mdm2 in the later phase of the response. Meanwhile, the concentration of p53 switches from moderate to high levels, contributing to apoptosis induction. We show that the presence of three mechanisms for Mdm2 downregulation, i.e. repression of mdm2 expression, inhibition of its nuclear entry and HIPK2-induced degradation, guarantees the apoptosis of irreparably damaged cells. Our results agree well with multiple experimental observations, and testable predictions are also made. This work advances our understanding of the regulation of p53 activity in the DDR and suggests that HIPK2 should be a significant target for cancer therapy.

scholarly journals RUNX Family Participates in the Regulation of p53-Dependent DNA Damage Response

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Toshinori Ozaki ◽  
Akira Nakagawara ◽  
Hiroki Nagase
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Death ◽  
Cell Cycle Arrest ◽  
Dna Damage Response ◽  
Apoptotic Cell ◽  
Genetic Alterations ◽  
Apoptotic Cell Death ◽  
Cycle Arrest ◽  
Damage Response

A proper DNA damage response (DDR), which monitors and maintains the genomic integrity, has been considered to be a critical barrier against genetic alterations to prevent tumor initiation and progression. The representative tumor suppressor p53 plays an important role in the regulation of DNA damage response. When cells receive DNA damage, p53 is quickly activated and induces cell cycle arrest and/or apoptotic cell death through transactivating its target genes implicated in the promotion of cell cycle arrest and/or apoptotic cell death such asp21WAF1,BAX, andPUMA. Accumulating evidence strongly suggests that DNA damage-mediated activation as well as induction of p53 is regulated by posttranslational modifications and also by protein-protein interaction. Loss of p53 activity confers growth advantage and ensures survival in cancer cells by inhibiting apoptotic response required for tumor suppression. RUNX family, which is composed of RUNX1, RUNX2, and RUNX3, is a sequence-specific transcription factor and is closely involved in a variety of cellular processes including development, differentiation, and/or tumorigenesis. In this review, we describe a background of p53 and a functional collaboration between p53 and RUNX family in response to DNA damage.

scholarly journals The absence of (TCAGGG)n repeats in some telomeres, combined with variable responses to NR2F2 depletion, suggest that this nuclear receptor plays an indirect role in the alternative lengthening of telomeres

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ahmed S. N. Alhendi ◽  
Nicola J. Royle
Keyword(s):  
Cell Lines ◽  
Dna Damage Response ◽  
Alternative Lengthening Of Telomeres ◽  
Direct Role ◽  
Cycle Arrest ◽  
Alternative Lengthening ◽  
Damage Response ◽  
Strand Invasion ◽  
Dna Strand ◽  
Telomere Lengthening

AbstractThe alternative lengthening of telomeres (ALT) facilitates telomere lengthening by a DNA strand invasion and copying mechanism. The nuclear receptors (NRs), NR2F2 and NR2C2, can bind to (TCAGGG)n variant repeats within telomeres and it has been proposed that this facilitates telomere interactions in ALT+ cells. Here we show that the frequency of cells with detectable NR2F2 and NR2C2 nuclear foci varies considerably between ALT+ cell lines and does not correlate with the level of protein expression. In addition, four of five ALT+ cell lines lack (TCAGGG)n repeats in some telomeres, indicating that direct NR binding does not play a role in ALT at these telomeres. NR2F2-depletion altered the abundance of C-circles and APBs but the direction of the response was inconsistent between three ALT+ cell lines. Moreover, transcriptome analysis following NR2F2-depletion in the ALT+ cell lines revealed different very responses. For example, NR2F2-depletion down-regulated many genes in U2OS cells, consistent with the cell cycle arrest and changes to ALT markers, but these features were not shared by the other two ALT+ cell lines. Among 86 ALT-associated genes, only MND1 showed consistent down-regulation across three NR2F2-depleted ALT+ cell lines. Altogether our data suggest that NR2F2 does not play a direct role in ALT and we speculate about an alternative role for this NR in a DNA damage response at telomeres.

scholarly journals Extracellular vesicles transfer nuclear Abl-dependent and radiation-induced miR-34c into unirradiated cells to cause bystander effects

2018 ◽  
Vol 29 (18) ◽  
pp. 2228-2242 ◽  
Author(s):  
Shubhra Rastogi ◽  
Amini Hwang ◽  
Josolyn Chan ◽  
Jean Y. J. Wang
Keyword(s):  
Extracellular Vesicles ◽  
Dna Damage Response ◽  
Nuclear Localization ◽  
Nuclear Localization Signal ◽  
Oxygen Species ◽  
Wild Type ◽  
Bystander Effects ◽  
Damage Response ◽  
Localization Signal ◽  
Radiation Induced

Ionizing radiation (IR) not only activates DNA damage response (DDR) in irradiated cells but also induces bystander effects (BE) in cells not directly targeted by radiation. How DDR pathways activated in irradiated cells stimulate BE is not well understood. We show here that extracellular vesicles secreted by irradiated cells (EV-IR), but not those from unirradiated controls (EV-C), inhibit colony formation in unirradiated cells by inducing reactive oxygen species (ROS). We found that µEV-IR from Abl nuclear localization signal–mutated ( Abl-µNLS) cells could not induce ROS, but expression of wild-type Abl restored that activity. Because nuclear Abl stimulates miR-34c biogenesis, we measured miR-34c in EV and found that its levels correlated with the ROS-inducing activity of EV. We then showed that EV from miR-34c minigene–transfected, but unirradiated cells induced ROS; and transfection with miR-34c-mimic, without radiation or EV addition, also induced ROS. Furthermore, EV-IR from miR34-family triple-knockout cells could not induce ROS, whereas EV-IR from wild-type cells could cause miR-34c increase and ROS induction in the miR-34 triple-knockout cells. These results establish a novel role for extracellular vesicles in transferring nuclear Abl-dependent and radiation-induced miR-34c into unirradiated cells to cause bystander oxidative stress.

scholarly journals Inhibition of p53 improves CRISPR/Cas - mediated precision genome editing

2017 ◽  
Author(s):  
Emma Haapaniemi ◽  
Sandeep Botla ◽  
Jenna Persson ◽  
Bernhard Schmierer ◽  
Jussi Taipale
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Homologous Recombination ◽  
Cell Cycle Arrest ◽  
Genome Editing ◽  
Dna Damage Response ◽  
Normal Cells ◽  
Cycle Arrest ◽  
Damage Response

AbstractWe report here that genome editing by CRISPR/Cas9 induces a p53-mediated DNA damage response and cell cycle arrest. Transient inhibition of p53 prevents this response, and increases the rate of homologous recombination more than five-fold. This provides a way to improve precision genome editing of normal cells, but warrants caution in using CRISPR for human therapies until the mechanism of the activation of p53 is elucidated.

scholarly journals Computational correction of off-targeting for CRISPR-Cas9 essentiality screens

2019 ◽  
Author(s):  
Alexendar R. Perez ◽  
Laura Sala ◽  
Richard K. Perez ◽  
Joana A. Vidigal
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Large Scale ◽  
Computational Method ◽  
Seamless Integration ◽  
Guide Rnas ◽  
Cycle Arrest ◽  
Damage Response

Off-target cleavage by Cas9 can confound measurements of cell proliferation/viability in CRISPR assays by eliciting a DNA-damage response that includes cell cycle arrest1-3. This gene-independent toxicity has been documented in large scale assays2-4 and shown to be a source of false-positives when libraries are populated by promiscuous guide RNAs (gRNAs)7. To address this, we developed CSC, a computational method to correct for the effect of specificity on gRNA depletion. We applied CSC to screening data from the Cancer Dependency Map and show that it significantly improves the specificity of CRISPR-Cas9 essentiality screens while preserving known gene essentialities even for genes targeted by highly pro-miscuous guides. We packaged CSC in a Python software to allow its seamless integration into current CRISPR analysis pipelines and improve the sensitivity of essentiality screens for repetitive genomic loci.

scholarly journals Nucleic Acid Immunity and DNA Damage Response: New Friends and Old Foes

2021 ◽  
Vol 12 ◽  
Author(s):  
Clara Taffoni ◽  
Alizée Steer ◽  
Johanna Marines ◽  
Hanane Chamma ◽  
Isabelle K. Vila ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nucleic Acid ◽  
Nucleic Acids ◽  
Dna Damage Response ◽  
Immune Activation ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Fine Tuning ◽  
Innate Immune Activation ◽  
Damage Response

The maintenance of genomic stability in multicellular organisms relies on the DNA damage response (DDR). The DDR encompasses several interconnected pathways that cooperate to ensure the repair of genomic lesions. Besides their repair functions, several DDR proteins have emerged as involved in the onset of inflammatory responses. In particular, several actors of the DDR have been reported to elicit innate immune activation upon detection of cytosolic pathological nucleic acids. Conversely, pattern recognition receptors (PRRs), initially described as dedicated to the detection of cytosolic immune-stimulatory nucleic acids, have been found to regulate DDR. Thus, although initially described as operating in specific subcellular localizations, actors of the DDR and nucleic acid immune sensors may be involved in interconnected pathways, likely influencing the efficiency of one another. Within this mini review, we discuss evidences for the crosstalk between PRRs and actors of the DDR. For this purpose, we mainly focus on cyclic GMP-AMP (cGAMP) synthetase (cGAS) and Interferon Gamma Inducible Protein 16 (IFI16), as major PRRs involved in the detection of aberrant nucleic acid species, and components of the DNA-dependent protein kinase (DNA-PK) complex, involved in the repair of double strand breaks that were recently described to qualify as potential PRRs. Finally, we discuss how the crosstalk between DDR and nucleic acid-associated Interferon responses cooperate for the fine-tuning of innate immune activation, and therefore dictate pathological outcomes. Understanding the molecular determinants of such cooperation will be paramount to the design of future therapeutic approaches.

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