scholarly journals cGAS is essential for cellular senescence

2017 ◽  
Vol 114 (23) ◽  
pp. E4612-E4620 ◽  
Author(s):  
Hui Yang ◽  
Hanze Wang ◽  
Junyao Ren ◽  
Qi Chen ◽  
Zhijian J. Chen
Keyword(s):  
Dna Damage ◽  
Cellular Senescence ◽  
Proliferating Cells ◽  
Antitumor Effects ◽  
Embryonic Fibroblasts ◽  
Dna Damaging Agents ◽  
Damage Response ◽  
Secretory Phenotype ◽  
Spontaneous Immortalization

Cellular senescence is a natural barrier to tumorigenesis and it contributes to the antitumor effects of several therapies, including radiation and chemotherapeutic drugs. Senescence also plays an important role in aging, fibrosis, and tissue repair. The DNA damage response is a key event leading to senescence, which is characterized by the senescence-associated secretory phenotype (SASP) that includes expression of inflammatory cytokines. Here we show that cGMP-AMP (cGAMP) synthase (cGAS), a cytosolic DNA sensor that activates innate immunity, is essential for senescence. Deletion of cGAS accelerated the spontaneous immortalization of mouse embryonic fibroblasts. cGAS deletion also abrogated SASP induced by spontaneous immortalization or DNA damaging agents, including radiation and etoposide. cGAS is localized in the cytoplasm of nondividing cells but enters the nucleus and associates with chromatin DNA during mitosis in proliferating cells. DNA damage leads to accumulation of damaged DNA in cytoplasmic foci that contain cGAS. In human lung adenocarcinoma patients, low expression of cGAS is correlated with poor survival. These results indicate that cGAS mediates cellular senescence and retards immortalization. This is distinct from, and complementary to, the role of cGAS in activating antitumor immunity.

scholarly journals Role of histone deacetylase 2 in epigenetics and cellular senescence: implications in lung inflammaging and COPD

2012 ◽  
Vol 303 (7) ◽  
pp. L557-L566 ◽  
Author(s):  
Hongwei Yao ◽  
Irfan Rahman
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Histone Deacetylase ◽  
Dna Damage Response ◽  
Cellular Senescence ◽  
Premature Aging ◽  
Epigenetic Mechanism ◽  
Histone Deacetylase 2 ◽  
Damage Response

Histone deacetylase 2 (HDAC2) is a class I histone deacetylase that regulates various cellular processes, such as cell cycle, senescence, proliferation, differentiation, development, apoptosis, and glucocorticoid function in inhibiting inflammatory response. HDAC2 has been shown to protect against DNA damage response and cellular senescence/premature aging via an epigenetic mechanism in response to oxidative stress. These phenomena are observed in patients with chronic obstructive pulmonary disease (COPD). HDAC2 is posttranslationally modified by oxidative/carbonyl stress imposed by cigarette smoke and oxidants, leading to its reduction via an ubiquitination-proteasome dependent degradation in lungs of patients with COPD. In this perspective, we have discussed the role of HDAC2 posttranslational modifications and its role in regulation of inflammation, histone/DNA epigenetic modifications, DNA damage response, and cellular senescence, particularly in inflammaging, and during the development of COPD. We have also discussed the potential directions for future translational research avenues in modulating lung inflammaging and cellular senescence based on epigenetic chromatin modifications in diseases associated with increased oxidative stress.

scholarly journals Autolysosomal degradation of cytosolic chromatin fragments antagonizes oxidative stress–induced senescence

2020 ◽  
Vol 295 (14) ◽  
pp. 4451-4463 ◽  
Author(s):  
Xiaojuan Han ◽  
Honghan Chen ◽  
Hui Gong ◽  
Xiaoqiang Tang ◽  
Ning Huang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cellular Senescence ◽  
Bafilomycin A1 ◽  
Nih3t3 Cells ◽  
Present Evidence ◽  
Chromatin Fragment ◽  
Secretory Phenotype ◽  
Peroxide Stress

Oxidative stress-induced DNA damage, the senescence-associated secretory phenotype (SASP), and impaired autophagy all are general features of senescent cells. However, the cross-talk among these events and processes is not fully understood. Here, using NIH3T3 cells exposed to hydrogen peroxide stress, we show that stress-induced DNA damage provokes the SASP largely via cytosolic chromatin fragment (CCF) formation, which activates a cascade comprising cGMP-AMP synthase (cGAS), stimulator of interferon genes protein (STING), NF-κB, and SASP, and that autolysosomal function inhibits this cascade. We found that CCFs accumulate in senescent cells with activated cGAS-STING-NF-κB signaling, promoting SASP and cellular senescence. We also present evidence that the persistent accumulation of CCFs in prematurely senescent cells is partially associated with a defect in DNA-degrading activity in autolysosomes and reduced abundance of activated DNase 2α. Intriguingly, we found that metformin- or rapamycin-induced activation of autophagy significantly lessened the size and levels of CCFs and repressed the activation of the cGAS-STING-NF-κB-SASP cascade and cellular senescence. These effects of autophagy activators indicated that autolysosomal function contributes to CCF clearance and SASP suppression, further supported by the fact that the lysosome inhibitor bafilomycin A1 blocked the role of autophagy-mediated CCF clearance and senescence repression.

scholarly journals Metabolic perturbation of epigenome by inhibiting S-adenosylhomocysteine hydrolase elicits senescence through DNA damage response in hepatoma cells

Tumor Biology ◽  
2017 ◽  
Vol 39 (5) ◽  
pp. 101042831769911 ◽  
Author(s):  
Guozhen Wu ◽  
Ning Wang ◽  
Ying Luo ◽  
Yanyan Zhang ◽  
Peng Wang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
Cellular Senescence ◽  
Genotoxic Stress ◽  
Hepatoma Cells ◽  
Adenosylhomocysteine Hydrolase ◽  
Dna Damaging Agents ◽  
Metabolic Perturbation ◽  
Damage Response

Cellular senescence is a key physiological barrier against tumor and represents an option for therapeutic intervention. One pivotal intracellular stimulus causing senescence is DNA damage response, while the senescence-associated heterochromatin in cancer limits the strength of the DNA damage response to endogenous genotoxic stress or DNA-damaging agents. Therefore, targeting the maintenance of compacted chromatin in cancer cells represents an optional intervention to improve the therapeutic efficacy in cancer treatment. Given a crosstalk between methionine cycle and histone methylation, we hypothesize that pharmacologically disrupting methylation potential, defined as the ratio of cellular S-adenosylmethionine to S-adenosylhomocysteine, could affect the chromatin structures in cancer cells and thus enhance their sensitivity to DNA damage response signaling. Our results showed that 3-deazaneplanocin A, a chemical inhibitor of S-adenosylhomocysteine hydrolase, elicited a typical cellular senescence in hepatoma cells. Therapy-induced senescence by 3-deazaneplanocin A was mediated through p53–p21 pathway and triggered by enhanced ataxia-telangiectasia mutated activation related to chromatin changes. In conclusion, our study demonstrated that metabolic perturbation of chromatin status in oncogene-activated cancers could be an optional intervention to sensitize DNA damage response signaling.

scholarly journals Mechanisms and Regulation of Cellular Senescence

2021 ◽  
Vol 22 (23) ◽  
pp. 13173
Author(s):  
Lauréline Roger ◽  
Fanny Tomas ◽  
Véronique Gire
Keyword(s):  
Dna Damage ◽  
Cellular Senescence ◽  
Cell Types ◽  
Feedback Loops ◽  
Cellular Structures ◽  
Damage Response ◽  
Different Types ◽  
Secretory Phenotype ◽  
Different Cell Types ◽  
Different Tissues

Cellular senescence entails a state of an essentially irreversible proliferative arrest in which cells remain metabolically active and secrete a range of pro-inflammatory and proteolytic factors as part of the senescence-associated secretory phenotype. There are different types of senescent cells, and senescence can be induced in response to many DNA damage signals. Senescent cells accumulate in different tissues and organs where they have distinct physiological and pathological functions. Despite this diversity, all senescent cells must be able to survive in a nondividing state while protecting themselves from positive feedback loops linked to the constant activation of the DNA damage response. This capacity requires changes in core cellular programs. Understanding how different cell types can undergo extensive changes in their transcriptional programs, metabolism, heterochromatin patterns, and cellular structures to induce a common cellular state is crucial to preventing cancer development/progression and to improving health during aging. In this review, we discuss how senescent cells continuously evolve after their initial proliferative arrest and highlight the unifying features that define the senescent state.

scholarly journals Fisetin inhibits proliferation of pancreatic adenocarcinoma by inducing DNA damage via RFXAP/KDM4A-dependent histone H3K36 demethylation

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Guoping Ding ◽  
Xiaodong Xu ◽  
Dan Li ◽  
Yuhao Chen ◽  
Weimin Wang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Pancreatic Adenocarcinoma ◽  
Dna Damage Response ◽  
Luciferase Reporter ◽  
Regulation Mechanism ◽  
Antitumor Effects ◽  
Inhibition Of Proliferation ◽  
Pancreatic Cancer Cells ◽  
Damage Response

Abstract Pancreatic adenocarcinoma (PDAC) is an extremely malignant tumor that is associated with low survival rates. Fisetin is a natural flavonoid that shows diverse antitumor effects, including DNA damage, in various cancers. Increasing studies have demonstrated that epigenetic modifications play critical roles in DNA-damage response. However, the epigenetic regulation mechanism of fisetin in cancers is hardly studied. RFXAP is a critical transcription factor for MHC II molecules, however, its transcriptional role in PDAC is poorly understood. The anti-PDAC effect of fisetin was measured by CCK-8, flow cytometry, xenograft tumor nude mice model. DNA-damage levels were examined by immunofluorescence. Bioinformatics analysis was used to examine the expression of RFXAP and other genes involved in DNA-damage response. ChIP sequencing was used to explore the transcriptional role of RFXAP. The expression of target gene KDM4A was measured by qRT-PCR and western blots. KDM4A promoter activity was analyzed using dual-luciferase reporter assay. RFXAP overexpressing or silencing of PDAC cells was used to explore the effect of RFXAP in DNA damage induced by fisetin. We found that fisetin inhibited cell proliferation and induced DNA damage and S-phase arrest in PDAC. Expression of RFXAP and other DNA-damage response genes were upregulated by fisetin. We revealed that RFXAP expression was relatively low in PDAC and correlated with tumor stage and poor prognosis. Then we explored the transcriptional role of RFXAP and found that RFXAP targeted KDM4A, a special demethylase specific for tri- and dimethylated histone H3K36. We found that overexpression of RFXAP upregulated KDM4A and attenuated methylation of H3K36, thereby impairing DNA repair and enhancing the DNA damage induced by fisetin, while RFXAP silencing showed the opposite effect. We also found the function of fisetin in enhancing the effect of chemotherapy on pancreatic cancer cells. Our findings revealed that fisetin induced DNA damage via RFXAP/KDM4A-dependent histone H3K36 demethylation, thus causing inhibition of proliferation in PDAC.

scholarly journals DNA damage response activation in mouse embryonic fibroblasts undergoing replicative senescence and following spontaneous immortalization

Cell Cycle ◽  
2008 ◽  
Vol 7 (22) ◽  
pp. 3601-3606 ◽  
Author(s):  
Raffaella Di Micco ◽  
Angelo Cicalese ◽  
Marzia Fumagalli ◽  
Miryana Dobreva ◽  
Alessandro Verrecchia ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Replicative Senescence ◽  
Mouse Embryonic Fibroblasts ◽  
Embryonic Fibroblasts ◽  
Damage Response ◽  
Spontaneous Immortalization ◽  
Response Activation

scholarly journals The Paradoxical Role of Cellular Senescence in Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Jing Yang ◽  
Mengmeng Liu ◽  
Dongchun Hong ◽  
Musheng Zeng ◽  
Xing Zhang
Keyword(s):  
Cellular Senescence ◽  
Tumor Development ◽  
Dependent Manner ◽  
Proliferating Cells ◽  
Cancer Aggressiveness ◽  
Suppressor Mechanism ◽  
Secretory Phenotype ◽  
The One ◽  
Inappropriate Expression

Cellular senescence occurs in proliferating cells as a consequence of various triggers including telomere shortening, DNA damage, and inappropriate expression of oncogenes. The senescent state is accompanied by failure to reenter the cell cycle under mitotic stimulation, resistance to cell death and enhanced secretory phenotype. A growing number of studies have convincingly demonstrated a paradoxical role for spontaneous senescence and therapy-induced senescence (TIS), that senescence may involve both cancer prevention and cancer aggressiveness. Cellular senescence was initially described as a physiological suppressor mechanism of tumor cells, because cancer development requires cell proliferation. However, there is growing evidence that senescent cells may contribute to oncogenesis, partly in a senescence-associated secretory phenotype (SASP)-dependent manner. On the one hand, SASP prevents cell division and promotes immune clearance of damaged cells, thereby avoiding tumor development. On the other hand, SASP contributes to tumor progression and relapse through creating an immunosuppressive environment. In this review, we performed a review to summarize both bright and dark sides of senescence in cancer, and the strategies to handle senescence in cancer therapy were also discussed.

scholarly journals Autophagy: A Player in response to Oxidative Stress and DNA Damage

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Serena Galati ◽  
Christian Boni ◽  
Maria Carla Gerra ◽  
Mirca Lazzaretti ◽  
Annamaria Buschini
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Unfolded Proteins ◽  
Cycle Arrest ◽  
Dna Damaging Agents ◽  
Damage Response ◽  
Cellular Stressors ◽  
Precise Role ◽  
Stress Accumulation

Autophagy is a catabolic pathway activated in response to different cellular stressors, such as damaged organelles, accumulation of misfolded or unfolded proteins, ER stress, accumulation of reactive oxygen species, and DNA damage. Some DNA damage sensors like FOXO3a, ATM, ATR, and p53 are known to be important autophagy regulators, and autophagy seems therefore to have a role in DNA damage response (DDR). Recent studies have partly clarified the pathways that induce autophagy during DDR, but its precise role is still not well known. Previous studies have shown that autophagy alterations induce an increase in DNA damage and in the occurrence of tumor and neurodegenerative diseases, highlighting its fundamental role in the maintenance of genomic stability. During DDR, autophagy could act as a source of energy to maintain cell cycle arrest and to sustain DNA repair activities. In addition, autophagy seems to play a role in the degradation of components involved in the repair machinery. In this paper, molecules which are able to induce oxidative stress and/or DNA damage have been selected and their toxic and genotoxic effects on the U937 cell line have been assessed in the presence of the single compounds and in concurrence with an inhibitor (chloroquine) or an inducer (rapamycin) of autophagy. Our data seem to corroborate the fundamental role of this pathway in response to direct and indirect DNA-damaging agents. The inhibition of autophagy through chloroquine had no effect on the genotoxicity induced by the tested compounds, but it led to a high increase of cytotoxicity. The induction of autophagy, through cotreatment with rapamycin, reduced the genotoxic activity of the compounds. The present study confirms the cytoprotective role of autophagy during DDR; its inhibition can sensitize cancer cells to DNA-damaging agents. The modulation of this pathway could therefore be an innovative approach able to reduce the toxicity of many compounds and to enhance the activity of others, including anticancer drugs.

scholarly journals Evidence for a role of the histone deacetylase SIRT6 in DNA damage response of multiple myeloma cells

Blood ◽  
2016 ◽  
Vol 127 (9) ◽  
pp. 1138-1150 ◽  
Author(s):  
Michele Cea ◽  
Antonia Cagnetta ◽  
Sophia Adamia ◽  
Chirag Acharya ◽  
Yu-Tzu Tai ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dna Damage ◽  
Enzymatic Activity ◽  
Histone Deacetylase ◽  
Dna Damage Response ◽  
Myeloma Cells ◽  
Dna Damaging Agents ◽  
Key Points ◽  
Damage Response

Key Points SIRT6 is highly expressed in multiple myeloma cells and blocks expression of ERK-regulated genes. Targeting SIRT6 enzymatic activity sensitizes multiple myeloma cells to DNA-damaging agents.

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