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1.
The impact of oxidative stress damage induced by the environmental stressors on COVID-19.
Bakadia, BM, Boni, BOO, Ahmed, AAQ, Yang, G
Life sciences. 2021;:118653
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Abstract
The ongoing pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a substantial stressor that is greatly impacting environmental sustainability. Besides, the different pre-existing environmental stressors and coronavirus disease-2019 (COVID-19)-related stressors are further worsening the effects of the viral disease by inducing the generation of oxidative stress. The generated oxidative stress results in nucleic acid damage associated with viral mutations, that could potentially reduce the effectiveness of COVID-19 management, including the vaccine approach. The current review is aimed to overview the impact of the oxidative stress damage induced by various environmental stressors on COVID-19. The available data regarding the COVID-19-related stressors and the effects of oxidative stress damage induced by the chronic stress, exposure to free radicals, and malnutrition are also analyzed to showcase the promising options, which could be investigated further for sustainable control of the pandemic.
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Endosomal trafficking and DNA damage checkpoint kinases dictate survival to replication stress by regulating amino acid uptake and protein synthesis.
Ajazi, A, Bruhn, C, Shubassi, G, Lucca, C, Ferrari, E, Cattaneo, A, Bachi, A, Manfrini, N, Biffo, S, Martini, E, et al
Developmental cell. 2021;(18):2607-2622.e6
Abstract
Atg6Beclin 1 mediates autophagy and endosomal trafficking. We investigated how Atg6 influences replication stress. Combining genetic, genomic, metabolomic, and proteomic approaches, we found that the Vps34-Vps15-Atg6Beclin 1-Vps38UVRAG-phosphatydilinositol-3 phosphate (PtdIns(3)P) axis sensitizes cells to replication stress by favoring the degradation of plasma membrane amino acid (AA) transporters via endosomal trafficking and ESCRT proteins, while the PtdIns(3)P phosphatases Ymr1 and Inp53 promote survival to replication stress by reversing this process. An impaired AA uptake triggers activation of Gcn2, which attenuates protein synthesis by phosphorylating eIF2α. Mec1Atr-Rad53Chk1/Chk2 activation during replication stress further hinders translation efficiency by counteracting eIF2α dephosphorylation through Glc7PP1. AA shortage-induced hyperphosphorylation of eIF2α inhibits the synthesis of 65 stress response proteins, thus resulting in cell sensitization to replication stress, while TORC1 promotes cell survival. Our findings reveal an integrated network mediated by endosomal trafficking, translational control pathways, and checkpoint kinases linking AA availability to the response to replication stress.
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An insight into understanding the coupling between homologous recombination mediated DNA repair and chromatin remodeling mechanisms in plant genome: an update.
Banerjee, S, Roy, S
Cell cycle (Georgetown, Tex.). 2021;(18):1760-1784
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Abstract
Plants, with their obligatory immobility, are vastly exposed to a wide range of environmental agents and also various endogenous processes, which frequently cause damage to DNA and impose genotoxic stress. These factors subsequently increase genome instability, thus affecting plant growth and productivity. Therefore, to survive under frequent and extreme environmental stress conditions, plants have developed highly efficient and powerful defense mechanisms to repair the damages in the genome for maintaining genome stability. Such multi-dimensional signaling response, activated in presence of damage in the DNA, is collectively known as DNA Damage Response (DDR). DDR plays a crucial role in the remarkably efficient detection, signaling, and repair of damages in the genome for maintaining plant genome stability and normal growth responses. Like other highly advanced eukaryotic systems, chromatin dynamics play a key role in regulating cell cycle progression in plants through remarkable orchestration of environmental and developmental signals. The regulation of chromatin architecture and nucleosomal organization in DDR is mainly modulated by the ATP dependent chromatin remodelers (ACRs), chromatin modifiers, and histone chaperones. ACRs are mainly responsible for transcriptional regulation of several homologous recombination (HR) repair genes in plants under genotoxic stress. The HR-based repair of DNA damage has been considered as the most error-free mechanism of repair and represents one of the essential sources of genetic diversity and new allelic combinations in plants. The initiation of DDR signaling and DNA damage repair pathway requires recruitment of epigenetic modifiers for remodeling of the damaged chromatin while accumulating evidence has shown that chromatin remodeling and DDR share part of the similar signaling pathway through the altered epigenetic status of the associated chromatin region. In this review, we have integrated information to provide an overview on the association between chromatin remodeling mediated regulation of chromatin structure stability and DDR signaling in plants, with emphasis on the scope of the utilization of the available knowledge for the improvement of plant health and productivity.Abbreviation: ADH: Alcohol Dehydrogenase; AGO2: Argonaute 2; ARP: Actin-Related Protein; ASF:1- Anti-Silencing Function-1; ATM: Ataxia Telangiectasia Mutated; ATR: ATM and Rad3- Related; AtSWI3c: Arabidopsis thaliana Switch 3c; ATXR5: Arabidopsis Trithorax-Related5; ATXR6: Arabidopsis Trithorax-Related6; BER: Base Excision Repair; BRCA1: Breast Cancer Associated 1; BRM: BRAHMA; BRU1: BRUSHY1; CAF:1- Chromatin Assembly Factor-1; CHD: Chromodomain Helicase DNA; CHR5: Chromatin Remodeling Protein 5; CHR11/17: Chromatin Remodeling Protein 11/17; CIPK11- CBL- Interacting Protein Kinase 11; CLF: Curly Leaf; CMT3: Chromomethylase 3; COR15A: Cold Regulated 15A; COR47: Cold Regulated 47; CRISPR Clustered Regulatory Interspaced Short Palindromic Repeats; DDM1: Decreased DNA Methylation1; DRR: DNA Repair and Recombination; DSBs: Double-Strand Breaks; DDR: DNA Damage Response; EXO1: Exonuclease 1; FAS1/2: Fasciata1/2; FACT Facilitates Chromatin Transcription; FT: Flowering Locus T; GMI1: Gamma-Irradiation And Mitomycin C Induced 1; HAC1: Histone Acetyltransferase of the CBP Family 1; HAM1: Histone Acetyltransferase of the MYST Family 1; HAM2: Histone Acetyltransferase of the MYST Family 2; HAF1: Histone Acetyltransferase of the TAF Family 1; HAT: Histone Acetyl Transferase; HDA1: Histone Deacetylase 1; HDA6: Histone Deacetylase 6; HIRA Histone Regulatory Homolog A; HR- Homologous recombination; HAS: Helicase SANT Associated; HSS: HAND-SLANT-SLIDE; ICE1: Inducer of CBF Expression 1; INO80: Inositol Requiring Mutant 80; ISW1: Imitation Switch 1; KIN1/2: Kinase 1 /2; MET1: Methyltransferase 1; MET2: Methyltransferase 2; MINU MINUSCULE; MMS: Methyl Methane Sulfonate; MMS21: Methyl Methane Sulfonate Sensitivity 21; MRN: MRE11, RAD50 and NBS1; MSI1: Multicopy Suppressor Of Ira1; NAP1: Nucleosome Assembly Protein 1; NRP1/NRP2: NAP1-Related Protein; NER: Nucleotide Excision Repair; NHEJ Non-Homologous End Joining; PARP1: Poly-ADP Ribose Polymerase; PIE1: Photoperiod Independent Early Flowering 1; PIKK Phosphoinositide 3-Kinase-Like Kinase; PKL: PICKLE; PKR1/2: PICKLE Related 1/2; RAD: Radiation Sensitive Mutant; RD22: Responsive To Desiccation 22; RD29A: Responsive To Desiccation 29A; ROS: Reactive Oxygen Species; ROS1: Repressor of Silencing 1; RPA1E: Replication Protein A 1E; SANT Swi3, Ada2, N-Cor and TFIIIB; SEP3: SEPALLATA3; SCC3: Sister Chromatid Cohesion Protein 3; SMC1: Structural Maintenance of Chromosomes Protein 1; SMC3: Structural Maintenance of Chromosomes Protein 3; SOG1: Suppressor of Gamma Response 1; SWC6: SWR1 Complex Subunit 6; SWR1: SWI2/SNF2-Related 1; SYD: SPLAYED; SMC5: Structural Maintenance of Chromosome 5; SWI/SNF: Switch/Sucrose Non-Fermentable; TALENs: Transcription Activators Like Effector Nucleases; TRRAP Transformation/Transactivation Domain-Associated Protein; ZFNs: Zinc Finger Nucleases.
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4.
Integrated genomic-metabolic classification of acute myeloid leukemia defines a subgroup with NPM1 and cohesin/DNA damage mutations.
Simonetti, G, Mengucci, C, Padella, A, Fonzi, E, Picone, G, Delpino, C, Nanni, J, De Tommaso, R, Franchini, E, Papayannidis, C, et al
Leukemia. 2021;(10):2813-2826
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Abstract
Although targeting of cell metabolism is a promising therapeutic strategy in acute myeloid leukemia (AML), metabolic dependencies are largely unexplored. We aimed to classify AML patients based on their metabolic landscape and map connections between metabolic and genomic profiles. Combined serum and urine metabolomics improved AML characterization compared with individual biofluid analysis. At intracellular level, AML displayed dysregulated amino acid, nucleotide, lipid, and bioenergetic metabolism. The integration of intracellular and biofluid metabolomics provided a map of alterations in the metabolism of polyamine, purine, keton bodies and polyunsaturated fatty acids and tricarboxylic acid cycle. The intracellular metabolome distinguished three AML clusters, correlating with distinct genomic profiles: NPM1-mutated(mut), chromatin/spliceosome-mut and TP53-mut/aneuploid AML that were confirmed by biofluid analysis. Interestingly, integrated genomic-metabolic profiles defined two subgroups of NPM1-mut AML. One was enriched for mutations in cohesin/DNA damage-related genes (NPM1/cohesin-mut AML) and showed increased serum choline + trimethylamine-N-oxide and leucine, higher mutation load, transcriptomic signatures of reduced inflammatory status and better ex-vivo response to EGFR and MET inhibition. The transcriptional differences of enzyme-encoding genes between NPM1/cohesin-mut and NPM1-mut allowed in silico modeling of intracellular metabolic perturbations. This approach predicted alterations in NAD and purine metabolism in NPM1/cohesin-mut AML that suggest potential vulnerabilities, worthy of being therapeutically explored.
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Deferasirox reduces oxidative DNA damage in bone marrow cells from myelodysplastic patients and improves their differentiation capacity.
Jiménez-Solas, T, López-Cadenas, F, Aires-Mejía, I, Caballero-Berrocal, JC, Ortega, R, Redondo, AM, Sánchez-Guijo, F, Muntión, S, García-Martín, L, Albarrán, B, et al
British journal of haematology. 2019;(1):93-104
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Abstract
Patients with low-risk myelodysplastic syndromes (MDS) usually develop iron overload. This leads to a high level of oxidative stress in the bone marrow (BM) and increases haematopoietic cell dysfunction. Our objective was to analyse whether chelation with deferasirox (DFX) alleviates the consequences of oxidative stress and improves BM cell functionality. We analysed 13 iron-overloaded MDS patients' samples before and 4-10 months after treatment with DFX. Using multiparametric flow cytometry analysis, we measured intracellular reactive oxygen species (ROS), DNA oxidation and double strand breaks. Haematopoietic differentiation capacity was analysed by colony-forming unit (CFU) assays. Compared to healthy donors, MDS showed a higher level of intracellular ROS and DNA oxidative damage in BM cells. DNA oxidative damage decreased following DFX treatment. Furthermore, the clonogenic assays carried out before treatment suggest an impaired haematopoietic differentiation. DFX seems to improve this capacity, as illustrated by a decreased cluster/CFU ratio, which reached values similar to controls. We conclude that BM cells from MDS are subject to higher oxidative stress conditions and show an impaired haematopoietic differentiation. These adverse features seem to be partially rectified after DFX treatment.
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Sub-optimal Application of a High SPF Sunscreen Prevents Epidermal DNA Damage in Vivo.
Young, AR, Greenaway, J, Harrison, GI, Lawrence, KP, Sarkany, R, Douki, T, Boyer, F, Josse, G, Questel, E, Monteil, C, et al
Acta dermato-venereologica. 2018;(9):880-887
Abstract
The cyclobutane pyrimidine dimer (CPD) is a potentially mutagenic DNA photolesion that is the basis of most skin cancers. There are no data on DNA protection by sunscreens under typical conditions of use. The study aim was to determine such protection, in phototypes I/II, with representative sunscreen-user application. A very high SPF formulation was applied at 0.75, 1.3 and 2.0 mg/cm2. Unprotected control skin was exposed to 4 standard erythema doses (SED) of solar simulated UVR, and sunscreen-treated sites to 30 SED. Holiday behaviour was also simulated by UVR exposure for 5 consecutive days. Control skin received 1 SED daily, and sunscreen-treated sites received 15 (all 3 application thicknesses) or 30 (2.0 mg/cm2) SED daily. CPD were assessed by quantitative HPLC-tandem mass spectrometry (HPLC-MS/MS) and semi-quantitative immunostaining. In comparison with unprotected control sites, sunscreen significantly (p ≤ 0.001-0.05) reduced DNA damage at 1.3 and 2.0 mg/cm2 in all cases. However, reduction with typical sunscreen use (0.75 mg/cm2) was non-significant, with the exception of HPLC-MS/MS data for the 5-day study (p <0.001). Overall, these results support sunscreen use as a strategy to reduce skin cancer, and demonstrate that public health messages must stress better sunscreen application to get maximal benefit.
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Impact of a (poly)phenol-rich extract from the brown algae Ascophyllum nodosum on DNA damage and antioxidant activity in an overweight or obese population: a randomized controlled trial.
Baldrick, FR, McFadden, K, Ibars, M, Sung, C, Moffatt, T, Megarry, K, Thomas, K, Mitchell, P, Wallace, JMW, Pourshahidi, LK, et al
The American journal of clinical nutrition. 2018;(4):688-700
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Abstract
BACKGROUND Epidemiologic evidence suggests that a diet rich in (poly)phenols has beneficial effects on many chronic diseases. Brown seaweed is a rich source of (poly)phenols. OBJECTIVE The aim of this study was to investigate the bioavailability and effect of a brown seaweed (Ascophyllum nodosum) (poly)phenol extract on DNA damage, oxidative stress, and inflammation in vivo. DESIGN A randomized, double-blind, placebo-controlled crossover trial was conducted in 80 participants aged 30-65 y with a body mass index (in kg/m2) ≥25. The participants consumed either a 400-mg capsule containing 100 mg seaweed (poly)phenol and 300 mg maltodextrin or a 400-mg maltodextrin placebo control capsule daily for an 8-wk period. Bioactivity was assessed with a panel of blood-based markers including lymphocyte DNA damage, plasma oxidant capacity, C-reactive protein (CRP), and inflammatory cytokines. To explore the bioavailability of seaweed phenolics, an untargeted metabolomics analysis of urine and plasma samples after seaweed consumption was determined by ultra-high-performance liquid chromatography-high-resolution mass spectrometry. RESULTS Consumption of the seaweed (poly)phenols resulted in a modest decrease in DNA damage but only in a subset of the total population who were obese. There were no significant changes in CRP, antioxidant status, or inflammatory cytokines. We identified phlorotannin metabolites that are considered potential biomarkers of seaweed consumption including pyrogallol/phloroglucinol-sulfate, hydroxytrifurahol A-glucuronide, dioxinodehydroeckol-glucuronide, diphlorethol sulfates, C-O-C dimer of phloroglucinol sulfate, and C-O-C dimer of phloroglucinol. CONCLUSIONS To the best of our knowledge, this work represents the first comprehensive study investigating the bioactivity and bioavailability of seaweed (poly)phenolics in human participants. We identified several potential biomarkers of seaweed consumption. Intriguingly, the modest improvements in DNA damage were observed only in the obese subset of the total population. The subgroup analysis should be considered exploratory because it was not preplanned; therefore, it was not powered adequately. Elucidation of the biology underpinning this observation will require participant stratification according to weight in future studies. This trial was registered at clinicaltrials.gov as NCT02295878.
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Translation acrobatics: how cancer cells exploit alternate modes of translational initiation.
Sriram, A, Bohlen, J, Teleman, AA
EMBO reports. 2018;(10)
Abstract
Recent work has brought to light many different mechanisms of translation initiation that function in cells in parallel to canonical cap-dependent initiation. This has important implications for cancer. Canonical cap-dependent translation initiation is inhibited by many stresses such as hypoxia, nutrient limitation, proteotoxic stress, or genotoxic stress. Since cancer cells are often exposed to these stresses, they rely on alternate modes of translation initiation for protein synthesis and cell growth. Cancer mutations are now being identified in components of the translation machinery and in cis-regulatory elements of mRNAs, which both control translation of cancer-relevant genes. In this review, we provide an overview on the various modes of non-canonical translation initiation, such as leaky scanning, translation re-initiation, ribosome shunting, IRES-dependent translation, and m6A-dependent translation, and then discuss the influence of stress on these different modes of translation. Finally, we present examples of how these modes of translation are dysregulated in cancer cells, allowing them to grow, to proliferate, and to survive, thereby highlighting the importance of translational control in cancer.
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Effect of Red Ginseng on Genotoxicity and Health-Related Quality of Life after Adjuvant Chemotherapy in Patients with Epithelial Ovarian Cancer: A Randomized, Double Blind, Placebo-Controlled Trial.
Kim, HS, Kim, MK, Lee, M, Kwon, BS, Suh, DH, Song, YS
Nutrients. 2017;(7)
Abstract
We evaluated the effect of red ginseng on toxicity, health-related quality of life (HRQL) and survival after adjuvant chemotherapy in patients with epithelial ovarian cancer (EOC). A total of 30 patients with EOC were randomly assigned to placebo (n = 15) and red ginseng groups (n = 15). All patients took placebo or red ginseng (3000 mg/day) for three months. Then, we compared changes of genotoxicity, HRQL and survival between the two groups. As a result, red ginseng reduced micronuclei yield in comparison with placebo despite no difference of binucleated cells index. Although red ginseng increased serum levels of alanine aminotransferase and aspartate aminotransferase significantly, they were within the normal value. Moreover, there were no differences in adverse events between placebo and red ginseng groups. In terms of HRQL, red ginseng was associated with improved emotional functioning and decreased symptoms of fatigue, nausea and vomiting, and dyspnea, reduced anxiety and interference affecting life and improved daytime somnolence. However, there was no effect of red ginseng on prognosis of EOC. Conclusively, red ginseng may be safe and effective to reduce genotoxicity and improve HRQL despite no benefit of survival in patients with EOC who received chemotherapy.
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Ectoine can enhance structural changes in DNA in vitro.
Meyer, S, Schröter, MA, Hahn, MB, Solomun, T, Sturm, H, Kunte, HJ
Scientific reports. 2017;(1):7170
Abstract
Strand breaks and conformational changes of DNA have consequences for the physiological role of DNA. The natural protecting molecule ectoine is beneficial to entire bacterial cells and biomolecules such as proteins by mitigating detrimental effects of environmental stresses. It was postulated that ectoine-like molecules bind to negatively charged spheres that mimic DNA surfaces. We investigated the effect of ectoine on DNA and whether ectoine is able to protect DNA from damages caused by ultraviolet radiation (UV-A). In order to determine different isoforms of DNA, agarose gel electrophoresis and atomic force microscopy experiments were carried out with plasmid pUC19 DNA. Our quantitative results revealed that a prolonged incubation of DNA with ectoine leads to an increase in transitions from supercoiled (undamaged) to open circular (single-strand break) conformation at pH 6.6. The effect is pH dependent and no significant changes were observed at physiological pH of 7.5. After UV-A irradiation in ectoine solution, changes in DNA conformation were even more pronounced and this effect was pH dependent. We hypothesize that ectoine is attracted to the negatively charge surface of DNA at lower pH and therefore fails to act as a stabilizing agent for DNA in our in vitro experiments.