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 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 The role of antioxidants in restoring MAPK 14 and a DNA damage marker level following autophagy suppression

Open Biology ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 200253
Author(s):  
Abdalla Elbialy
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Oxidative Stress Marker ◽  
Signalling Pathways ◽  
Biological Processes ◽  
Bafilomycin A1 ◽  
Damage Response ◽  
Damage Marker

Autophagy is a lysosomal degradation mechanism for elimination and recycling of damaged intracellular organelles and proteins. Recent studies have shown that autophagy could help reduce oxidative stress by removing oxidized proteins and damaged mitochondria. Autophagy deficiency is associated with the disruption of many intracellular biological processes. Using bioinformatics tools and fibroblast immunostaining technology, I tried to investigate whether oxidative stress is involved in mediating the effect of autophagy suppression on certain cell biological processes and signalling pathways. Many pharmaceutical components have different modes of action to suppress autophagy. In this study, I performed analysis on autophagy suppression induced by neutralizing lysosomal pH (NH 4 Cl and bafilomycin A1). Bioinformatics analysis of GEO data, GSE60570 accession number, revealed that p38 signalling induction and DNA damage response are among the main disrupted signalling pathways in bafilomycin A1-treated RPE-1 cells. Likewise, fibroblast immunostaining showed that autophagy deficiency established by ammonium chloride (NH 4 Cl) has significantly increased P38 signalling, DNA damage marker (H2A.X), and oxidative stress marker (dityrosine). I therefore investigated the role of oxidative stress and whether antioxidants treatment could reverse autophagy suppression effects on p38 signalling and DNA damage response. Importantly, antioxidant treatment clearly restored P38 signalling and H2A.X levels in autophagy-suppressed fibroblast cells. Indicating that oxidative stress might be associated with the harmful effect of autophagy suppression.

scholarly journals Therapy-Induced Senescence As an Anti-Cancer and Immune-Stimulatory Strategy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4419-4419
Author(s):  
Diego Gilioli ◽  
Simona Fusco ◽  
Kety Giannetti ◽  
Valentina Gambacorta ◽  
Teresa Tavella ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
T Cells ◽  
Dna Damage Response ◽  
Cycle Arrest ◽  
Response To Chemotherapy ◽  
Damage Response ◽  
Senescence Program ◽  
Hla Molecules

Abstract Acute myeloid leukaemia (AML) is the most common type of leukaemia in elderly, for which the current gold standard of treatment is chemotherapy. Recently, it has been observed that AML blasts can activate the senescence program in response to chemotherapy (Therapy Induced Senescence, TIS). Cellular senescence is a stable and terminal state of growth arrest, often caused by nuclear DNA damage, associated with the transcriptional activation of a so-called Senescence Associated Secretory Phenotype (SASP), characterized, among others, by cytokines release, reported to promote immune-surveillance. Here we show that blasts, in response to chemotherapy, accumulate DNA damage and activate the senescence program, that in turn leads to HLA molecules upregulation, making them more prone to be cleared by T-cells. To evaluate TIS in AML blasts, we started by applying chemotherapy treatment (ARA-C) in six AML cell lines with different p53 status and FAB classification, observing reduction in proliferation rate and activation of DNA damage response pathways in the absence of overt apoptosis. We then quantified Senescence-Associated β-galactosidase (SA-βgal) activity and detected induction of senescence longitudinally with different extent. Accordingly, we observed the same features when applying ARA-C ex-vivo to primary AML samples collected at diagnosis. To delve deeper into the changes associated with the establishment of senescence in primary blasts, we performed RNA-seq analysis and observed an upregulation of pro-inflammatory genes (including IL1, IL6 and IL8) along with genes involved in immunogenicity. Investigating the biological significance of the transcriptional changes observed, we first reported an increase of HLA molecules on the surface of senescent blasts, as measured by FACS analyses. This observation prompted us to study the interaction between the immune system and senescent blasts, exploiting the Mixed Lymphocyte Reaction (MLR) assay. As expected, we detected a higher T-cell activation of both CD8+ and CD4+ subpopulations, accompanied by an increase in immunological synapses events and in apoptosis induction, when co-culturing chemotherapy treated blasts with T cells. In order to uncover the molecular mechanisms involved in TIS, we disentangled the role of DNA damage and cell cycle arrest in the phenotype observed comparing AML cell lines treatment with either ARA-C or the cdk4/6 inhibitor, which causes cell cycle arrest without inducing DNA damage. We found that HLA molecules overexpression is linked to the establishment of DNA damage response, however, when comparing acute to chronic ARA-C treatment, we observed that expression levels increased with treatment duration, suggesting that this feature is necessary but not sufficient to increase AML immunogenicity. Next, taking advantage of shRNAs (delivered by lentiviral vectors), we investigated deeper into the role of cell cylcle arrest. By stably knocking down p21, a crucial cell cycle inhibitor, we observed that ARA-C treated blasts had a reduced capacity of activating T-cell. Taken together, these observations point out to a crucial role for senescence in the improved immune-based clearance observed upon ARA-C treatment of blasts. Interestingly, a retrospective analysis showed that a cohort of patients clinically considered "responders" displayed a higher SA-βgal activity, further supporting the idea that senescence establishment in AML may act as a tumour suppressor mechanism. Overall, our study provides mechanistic insights into the biological and cellular response of AML cells to TIS and presents senescence as a positive mechanism able to promote AML eradication. This opens new lines of research aimed to develop novel therapeutic approaches against AML, exploiting senescence-induced features. Disclosures Vago: Moderna Therapeutics: Research Funding; GEN-DX: Patents & Royalties.

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.

scholarly journals The role of the α-tubulin acetyltransferase αTAT1 in the DNA damage response

2020 ◽  
Vol 133 (17) ◽  
pp. jcs246702
Author(s):  
Na Mi Ryu ◽  
Jung Min Kim
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Dna Damage Response ◽  
Protein A ◽  
Direct Repeat ◽  
Microtubule Organization ◽  
Cycle Arrest ◽  
Recombination Repair ◽  
Damage Response

ABSTRACTLysine 40 acetylation of α-tubulin (Ac-α-tubulin), catalyzed by the acetyltransferase αTAT1, marks stabilized microtubules. Recently, there is growing evidence to suggest crosstalk between the DNA damage response (DDR) and microtubule organization; we therefore investigated whether αTAT1 is involved in the DDR. Following treatment with DNA-damaging agents, increased levels of Ac-α-tubulin were detected. We also observed significant induction of Ac-α-tubulin after depletion of DNA repair proteins, suggesting that αTAT1 is positively regulated in response to DNA damage. Intriguingly, αTAT1 depletion decreased DNA damage-induced replication protein A (RPA) phosphorylation and foci formation. Moreover, DNA damage-induced cell cycle arrest was significantly delayed in αTAT1-depleted cells, indicating defective checkpoint activation. The checkpoint defects seen upon αTAT1 deficiency were restored by expression of wild-type αTAT1, but not by αTAT1-D157N (a catalytically inactive αTAT1), indicating that the role of αTAT1 in the DDR is dependent on enzymatic activity. Furthermore, αTAT1-depleted direct repeat GFP (DR-GFP) U2OS cells had a significant decrease in the frequency of homologous recombination repair. Collectively, our results suggest that αTAT1 may play an essential role in DNA damage checkpoints and DNA repair through its acetyltransferase activity.

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 On Broken Ne(c)ks and Broken DNA: The Role of Human NEKs in the DNA Damage Response

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 507
Author(s):  
Isadora Carolina Betim Pavan ◽  
Andressa Peres de Oliveira ◽  
Pedro Rafael Firmino Dias ◽  
Fernanda Luisa Basei ◽  
Luidy Kazuo Issayama ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Arrest ◽  
Dna Damage Response ◽  
Ataxia Telangiectasia ◽  
General Role ◽  
Cycle Arrest ◽  
Damage Response ◽  
Repair Pathways

NIMA-related kinases, or NEKs, are a family of Ser/Thr protein kinases involved in cell cycle and mitosis, centrosome disjunction, primary cilia functions, and DNA damage responses among other biological functional contexts in vertebrate cells. In human cells, there are 11 members, termed NEK1 to 11, and the research has mainly focused on exploring the more predominant roles of NEKs in mitosis regulation and cell cycle. A possible important role of NEKs in DNA damage response (DDR) first emerged for NEK1, but recent studies for most NEKs showed participation in DDR. A detailed analysis of the protein interactions, phosphorylation events, and studies of functional aspects of NEKs from the literature led us to propose a more general role of NEKs in DDR. In this review, we express that NEK1 is an activator of ataxia telangiectasia and Rad3-related (ATR), and its activation results in cell cycle arrest, guaranteeing DNA repair while activating specific repair pathways such as homology repair (HR) and DNA double-strand break (DSB) repair. For NEK2, 6, 8, 9, and 11, we found a role downstream of ATR and ataxia telangiectasia mutated (ATM) that results in cell cycle arrest, but details of possible activated repair pathways are still being investigated. NEK4 shows a connection to the regulation of the nonhomologous end-joining (NHEJ) repair of DNA DSBs, through recruitment of DNA-PK to DNA damage foci. NEK5 interacts with topoisomerase IIβ, and its knockdown results in the accumulation of damaged DNA. NEK7 has a regulatory role in the detection of oxidative damage to telomeric DNA. Finally, NEK10 has recently been shown to phosphorylate p53 at Y327, promoting cell cycle arrest after exposure to DNA damaging agents. In summary, this review highlights important discoveries of the ever-growing involvement of NEK kinases in the DDR pathways. A better understanding of these roles may open new diagnostic possibilities or pharmaceutical interventions regarding the chemo-sensitizing inhibition of NEKs in various forms of cancer and other diseases.

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