Chronic DNA Damage Research Articles

The role of chronic stress, tumor immunity, and DNA damage in cervical cancer

The role of chronic stress, tumor immunity, and DNA damage in cervical cancer

The senescence-associated secretory phenotype and its physiological and pathological implications.

Cellular senescence is a state of terminal growth arrest associated with the upregulation of different cell cycle inhibitors, mainly p16 and p21, structural and metabolic alterations, chronic DNA damage responses, and a hypersecretory state known as the senescence-associated secretory phenotype (SASP). The SASP is the major mediator of the paracrine effects of senescent cells in their tissue microenvironment and of various local and systemic biological functions. In this Review, we discuss the composition, dynamics and heterogeneity of the SASP as well as the mechanisms underlying its induction and regulation. We describe the various biological properties of the SASP, its beneficial and detrimental effects in different physiological and pathological settings, and its impact on overall health span. Finally, we discuss the use of the SASP as a biomarker and of SASP inhibitors as senomorphic interventions to treat cancer and other age-related conditions.

Gamma entrainment using audiovisual stimuli alleviates chemobrain pathology and cognitive impairment induced by chemotherapy in mice.

Patients with cancer undergoing chemotherapy frequently experience a neurological condition known as chemotherapy-related cognitive impairment, or "chemobrain," which can persist for the remainder of their lives. Despite the growing prevalence of chemobrain, both its underlying mechanisms and treatment strategies remain poorly understood. Recent findings suggest that chemobrain shares several characteristics with neurodegenerative diseases, including chronic neuroinflammation, DNA damage, and synaptic loss. We investigated whether a noninvasive sensory stimulation treatment we term gamma entrainment using sensory stimuli (GENUS), which has been shown to alleviate aberrant immune and synaptic pathologies in mouse models of neurodegeneration, could also mitigate chemobrain phenotypes in mice administered a chemotherapeutic drug. When administered concurrently with the chemotherapeutic agent cisplatin, GENUS alleviated cisplatin-induced brain pathology, promoted oligodendrocyte survival, and improved cognitive function in a mouse model of chemobrain. These effects persisted for up to 105 days after GENUS treatment, suggesting the potential for long-lasting benefits. However, when administered to mice 90 days after chemotherapy, GENUS treatment only provided limited benefits, indicating that it was most effective when used to prevent the progression of chemobrain pathology. Furthermore, we demonstrated that the effects of GENUS in mice were not limited to cisplatin-induced chemobrain but also extended to methotrexate-induced chemobrain. Collectively, these findings suggest that GENUS may represent a versatile approach for treating chemobrain induced by different chemotherapy agents.

Postbiotics in colorectal cancer: intervention mechanisms and perspectives.

Colorectal cancer (CRC) is a common malignancy affecting the gastrointestinal tract worldwide. The etiology and progression of CRC are related to factors such as environmental influences, dietary structure, and genetic susceptibility. Intestinal microbiota can influence the integrity of the intestinal mucosal barrier and modulate intestinal immunity by secreting various metabolites. Dysbiosis of the intestinal microbiota can affect the metabolites of the microbial, leading to the accumulation of toxic metabolites, which can trigger chronic inflammation or DNA damage and ultimately lead to cellular carcinogenesis and the development of CRC. Postbiotics are preparations of inanimate microorganisms or their components that are beneficial to the health of the host, with the main components including bacterial components (e.g., exopolysaccharides, teichoic acids, surface layer protein) and metabolites (e.g., short-chain fatty acids, tryptophan metabolite, bile acids, vitamins and enzymes). Compared with traditional probiotics, it has a more stable chemical structure and higher safety. In recent years, it has been demonstrated that postbiotics are involved in regulating intestinal microecology and improving the progression of CRC, which provides new ideas for the prevention and diagnosis of CRC. In this article, we review the changes in intestinal microbiota in different states of the gut and the mechanisms of anti-tumor activity of postbiotic-related components, and discuss the potential significance of postbiotics in the diagnosis and treatment of CRC. This reviews the changes and pathogenesis of intestinal microbiota in the development of CRC, and summarizes the relevant mechanisms of postbiotics in resisting the development of CRC in recent years, as well as the advantages and limitations of postbiotics in the treatment process of CRC.

Large Deletions, Cleavage of the Telomeric Repeat Sequence, and Reverse Transcriptase-Mediated DNA Damage Response Associated with Long Interspersed Element-1 ORF2p Enzymatic Activities.

L1 elements can cause DNA damage and genomic variation via retrotransposition and the generation of endonuclease-dependent DNA breaks. These processes require L1 ORF2p protein that contains an endonuclease domain, which cuts genomic DNA, and a reverse transcriptase domain, which synthesizes cDNA. The complete impact of L1 enzymatic activities on genome stability and cellular function remains understudied, and the spectrum of L1-induced mutations, other than L1 insertions, is mostly unknown. Using an inducible system, we demonstrate that an ORF2p containing functional reverse transcriptase is sufficient to elicit DNA damage response even in the absence of the functional endonuclease. Using a TK/Neo reporter system that captures misrepaired DNA breaks, we demonstrate that L1 expression results in large genomic deletions that lack any signatures of L1 involvement. Using an in vitro cleavage assay, we demonstrate that L1 endonuclease efficiently cuts telomeric repeat sequences. These findings support that L1 could be an unrecognized source of disease-promoting genomic deletions, telomere dysfunction, and an underappreciated source of chronic RT-mediated DNA damage response in mammalian cells. Our findings expand the spectrum of biological processes that can be triggered by functional and nonfunctional L1s, which have impactful evolutionary- and health-relevant consequences.

Transgenerational inheritance of methylmercury and vitamin A-induced toxicological effects in a Wistar rats environmental-based model

Mercury (Hg) and vitamin A (VitA) are two environmental factors with potential health impacts, especially during pregnancy and early childhood. Fish and seafood may present elevated levels of methylmercury (MeHg), the major Hg derivative, and VitA. This study aimed to evaluate the transgenerational effects of exposure to MeHg and/or VitA on epigenetic and toxicological parameters in a Wistar rat model. Our findings revealed persistent toxicological effects in generations F1 and F2 following low/mild doses of MeHg and/or VitA exposure during dams’ (F0) gestation and breastfeeding. Toxicological effects observed in F2 included chronic DNA damage, bone marrow toxicity, altered microglial content, reduced neuronal signal, and diminished male longevity. Sex-specific patterns were also observed. Co-exposure to MeHg and VitA showed both synergistic and antagonistic effects. Additionally, the study demonstrated that MeHg and VitA affected histone methylation and caused consistent effects in F2. While MeHg exposure has been associated with transgenerational inheritance effects in other organisms, this study provides the first evidence of transgenerational inheritance of MeHg and VitA-induced toxicological effects in rodents. Although the exact mechanism is not yet fully understood, these findings suggest that MeHg and VitA may perpetuate their impacts across generations. The study highlights the need for remedial policies and interventions to mitigate the potential health problems faced by future generations exposed to MeHg or VitA. Further research is warranted to investigate the transgenerational effects beyond F2 and determine the matrilineal or patrilineal inheritance patterns.

The entanglement of DNA damage and pattern recognition receptor signaling

Cells are under constant pressure to suppress DNA damage originating from both exogenous and endogenous sources. Cellular responses to DNA damage help to prevent mutagenesis and cell death that arises when DNA damage is either left unrepaired or repaired inaccurately. During the “acute phase” of DNA damage signaling, lesions are recognized, processed, and repaired to restore the primary DNA sequence whilst cell cycle checkpoints delay mitotic progression, cell death and the propagation of errors to daughter cells. Increasingly, there is recognition of a “chronic phase” of DNA damage signaling, exemplified by the secretion of dozens of cytokines days after the inciting damage event. In this review, we focus on the cellular origin of these chronic responses, the molecular pathways that control them and the increasing appreciation for the interconnection between acute and chronic DNA damage responses.

Roles of poly(ADP-ribose) polymerase 1 and mitophagy in progeroid syndromes as well as physiological ageing

Progeroid syndromes are characterized by clinical signs of premature ageing, which may contain several diseases such as Werner syndrome, Bloom syndrome, Rothmund-Thomson syndrome, Hutchinson-Gilford progeria syndrome, and Cockayne syndrome. These disorders may also exhibit some pathological involvements reminiscent of primary mitochondrial diseases. Emerging evidence has linked mitochondria even to physiological ageing. In addition, alterations in the maintenance pathway of mitochondria have been also deliberated as relevant in age-related diseases. In particular, mitophagy and its regulatory pathway might be key process for the homeostasis of mitochondria. Therefore, chronic DNA damage and/or the activation of poly[adenosine diphosphate (ADP)-ribose] polymerase 1 (PARP1) could be a threat to the mitochondrial alterations. The PARP1 is an enzyme responding to the DNA damage, which might be also involved in the mitophagy. Interestingly, the PARP1 has been reported to play an important role in the longevity of lifespan, which has attracted growing attention with the social development. This review may provide a rationalized overview of the involvement of mitochondrial oxidative stresses in genetically defined accelerated ageing, progeroid syndromes, physiological ageing, and/or age-related diseases for the innovative therapeutic approaches.

The DNA damage response pathway regulates the expression of the immune checkpoint CD47

CD47 is a cell surface ligand expressed on all nucleated cells. It is a unique immune checkpoint protein acting as “don’t eat me” signal to prevent phagocytosis and is constitutively overexpressed in many tumors. However, the underlying mechanism(s) for CD47 overexpression is not clear. Here, we show that irradiation (IR) as well as various other genotoxic agents induce elevated expression of CD47. This upregulation correlates with the extent of residual double-strand breaks (DSBs) as determined by γH2AX staining. Interestingly, cells lacking mre-11, a component of the MRE11-RAD50-NBS1 (MRN) complex that plays a central role in DSB repair, or cells treated with the mre-11 inhibitor, mirin, fail to elevate the expression of CD47 upon DNA damage. On the other hand, both p53 and NF-κB pathways or cell-cycle arrest do not play a role in CD47 upregualtion upon DNA damage. We further show that CD47 expression is upregulated in livers harvested from mice treated with the DNA-damage inducing agent Diethylnitrosamine (DEN) and in cisplatin-treated mesothelioma tumors. Hence, our results indicate that CD47 is upregulated following DNA damage in a mre-11-dependent manner. Chronic DNA damage response in cancer cells might contribute to constitutive elevated expression of CD47 and promote immune evasion.

Impacts of Telomeric Length, Chronic Hypoxia, Senescence, and Senescence-Associated Secretory Phenotype on the Development of Thoracic Aortic Aneurysm

Thoracic aortic aneurysm (TAA) is an age-related and life-threatening vascular disease. Telomere shortening is a predictor of age-related diseases, and its progression is associated with premature vascular disease. The aim of the present work was to investigate the impacts of chronic hypoxia and telomeric DNA damage on cellular homeostasis and vascular degeneration of TAA. We analyzed healthy and aortic aneurysm specimens (215 samples) for telomere length (TL), chronic DNA damage, and resulting changes in cellular homeostasis, focusing on senescence and apoptosis. Compared with healthy thoracic aorta (HTA), patients with tricuspid aortic valve (TAV) showed telomere shortening with increasing TAA size, in contrast to genetically predisposed bicuspid aortic valve (BAV). In addition, TL was associated with chronic hypoxia and telomeric DNA damage and with the induction of senescence-associated secretory phenotype (SASP). TAA-TAV specimens showed a significant difference in SASP-marker expression of IL-6, NF-κB, mTOR, and cell-cycle regulators (γH2AX, Rb, p53, p21), compared to HTA and TAA-BAV. Furthermore, we observed an increase in CD163+ macrophages and a correlation between hypoxic DNA damage and the number of aortic telocytes. We conclude that chronic hypoxia is associated with telomeric DNA damage and the induction of SASP in a diseased aortic wall, promising a new therapeutic target.

Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner.

Defects in nucleic acid metabolizing enzymes can lead to spontaneous but selective activation of either cGAS/STING or RIG-like receptor (RLR) signaling, causing type I interferon-driven inflammatory diseases. In these pathophysiological conditions, activation of the DNA sensor cGAS and IFN production are linked to spontaneous DNA damage. Physiological, or tonic, IFN signaling on the other hand is essential to functionally prime nucleic acid sensing pathways. Here, we show that low-level chronic DNA damage in mice lacking the Aicardi-Goutières syndrome gene SAMHD1 reduced tumor-free survival when crossed to a p53-deficient, but not to a DNA mismatch repair-deficient background. Increased DNA damage did not result in higher levels of type I interferon. Instead, we found that the chronic interferon response in SAMHD1-deficient mice was driven by the MDA5/MAVS pathway but required functional priming through the cGAS/STING pathway. Our work positions cGAS/STING upstream of tonic IFN signaling in Samhd1-deficient mice and highlights an important role of the pathway in physiological and pathophysiological innate immune priming.

Persistent DNA damage underlies tubular cell polyploidization and progression to chronic kidney disease in kidneys deficient in the DNA repair protein FAN1

Defective DNA repair pathways contribute to the development of chronic kidney disease (CKD) in humans. However, the molecular mechanisms underlying DNA damage-induced CKD pathogenesis are not well understood. Here, we investigated the role of tubular cell DNA damage in the pathogenesis of CKD using mice in which the DNA repair protein Fan1 was knocked out. The phenotype of these mice is orthologous to the human DNA damage syndrome, karyomegalic interstitial nephritis (KIN). Inactivation of Fan1 in kidney proximal tubule cells sensitized the kidneys to genotoxic and obstructive injury characterized by replication stress and persistent DNA damage response activity. Accumulation of DNA damage in Fan1 tubular cells induced epithelial dedifferentiation and tubular injury. Characteristic to KIN, cells with chronic DNA damage failed to complete mitosis and underwent polyploidization. Invitro and invivo studies showed that polyploidization was caused by the overexpression of DNA replication factors CDT1 and CDC6 in FAN1 deficient cells. Mechanistically, inhibiting DNA replication with Roscovitine reduced tubular injury, blocked the development of KIN and mitigated kidney function in these Fan1 knockout mice. Thus, our data delineate a mechanistic pathway by which persistent DNA damage in the kidney tubular cells leads to kidney injury and development of CKD. Furthermore, therapeutic modulation of cell cycle activity may provide an opportunity to mitigate the DNA damage response induced CKD progression.

Brazilian workers occupationally exposed to different toxic agents: A systematic review on DNA damage.

The evaluation of genotoxicity in workers exposed to different toxic agents is very important, especially considering the association between these exposures in a chronic context and DNA damage. Assessing biomarkers of exposure and, when possible, early biomarkers of effect, contributes to elucidating the potential toxic mechanisms involved in genotoxicity and its contribution to chronic non-communicable diseases. In Brazil, the biggest country in South America, workers are exposed to hazardous physical and chemical agents. Considering that these exposures occur, in most cases, throughout the worker's whole life, this is an important public health concern in Brazil. Therefore, this systematic review aims to analyze occupational exposure to chemical and physical agents and the association with DNA damage in studies carried out in Brazil from 1980 to 2021. A systematic and comprehensive literature search was performed in different databases based on occupational exposure to chemical and physical agents and DNA damage. Only full articles on studies that investigated experimental evidence on occupational exposure in Brazil and assessed DNA damage were included, amounting to 89 articles. Five main occupational exposure groups were identified: pesticides (36%), organic solvents (20%), dust and particles (16%), metals (11%), and ionizing radiation (6%). Another group called "others" included studies (11%) that did not fall into these main groups. It was found that comet assay and micronucleus tests are the most adopted methods to detect DNA damage. Occupational exposures were most associated with DNA damage. However, further improvements in study design would be needed to better characterize the association between biomonitoring and DNA damage, particularly to account for confounding factors.

Opposing roles of HDAC6 in liver regeneration and hepatocarcinogenesis

Histone deacetylase 6 (HDAC6), a deacetylase of p53, has emerged as a privileged inhibitory target for cancer therapy because of its deacetylating activity for p53 at K120 and K373/382. However, intricate roles of HDAC6 in hepatocellular carcinogenesis have been suggested by recent evidence, namely that HDAC6 ablation suppresses innate immunity, which plays critical roles in tumor immunosurveillance and antitumor immune responses. Therefore, it is valuable to determine whether HDAC6 ablation inhibits hepatocellular carcinogenesis using in vivo animal models. Here, we firstly showed that HDAC6 ablation increased K320 acetylation of p53, known as pro‐survival acetylation, in all tested animal models but did not always increase K120 and K373/382 acetylation of p53, known as pro‐apoptotic acetylation. HDAC6 ablation induced cellular senescence in primary MEFs and inhibited cell proliferation in HepG2 cells and liver regeneration after two‐thirds partial hepatectomy. However, the genetic ablation of HDAC6 did not inhibit hepatocarcinogenesis, but instead slightly enhanced it in two independent mouse models (DEN + HFD and DEN + TAA). Notably, HDAC6 ablation significantly promoted hepatocarcinogenesis in a multiple DEN treatment hepatocellular carcinoma (HCC) mouse model, mimicking chronic DNA damage in the liver, which correlated with hyperacetylation at K320 of p53 and a decrease in inflammatory cytokines and chemokines. Our data from three independent in vivo animal HCC models emphasize the importance of the complex roles of HDAC6 ablation in hepatocellular carcinogenesis, highlighting its immunosuppressive effects.

Potential Chemotherapeutic Effect of Selenium for Improved Canceration of Esophageal Cancer.

Esophageal squamous cell carcinoma is the most common type of esophageal cancer and accounts for 5% of malignant tumor deaths. Recent research suggests that chronic inflammation and DNA damage may drive the onset of esophageal squamous cell carcinoma, implying that lowering chronic inflammation and DNA damage compounds may provide chemo-prevention. According to epidemiological and experimental evidence, selenium is linked to a lower risk of several malignancies, including esophageal squamous cell carcinoma. However, its exact mechanism is still unclear. In the present study, we used cell lines and a 4-NQO mice model to explore the anti-cancer mechanism of four types of selenium. Our findings indicated that selenium inhibited the proliferation, colony formation, and ROS level of ESCC cell lines in a time-dependent manner. Intriguingly, selenium treatment impeded 4-NQO-induced high-grade intraepithelial neoplasia and reduced the number of positive inflammatory cells by preserving DNA from oxidative damage. In addition, selenium significantly decreased the expression of Ki-67 and induced apoptosis. This study demonstrates that selenium has a significant chemo-preventive effect on ESCC by reducing high-grade dysplasia to low-grade dysplasia. For the first time, selenium was shown to slow down the progression of esophageal cancer by lowering inflammation and oxidative DNA damage.

Altered oxidative DNA damage repair systems in muscles of old mice: role in the age‐related increase in muscle production of cytokines/chemokines

An increased presence of the oxidised DNA base lesion 8‐oxo‐7,8‐dihydroguanine (8‐oxoG) is seen in muscles of old mice. 8‐oxoG is repaired by the 8‐oxoguanine DNA glycosylase‐1 (OGG1)‐initiated DNA base excision repair pathway, a process proposed to lead to activation of nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐kB). We hypothesised that chronic oxidative DNA damage in muscles of old mice leads to the chronic increase in activation of NF‐kB by OGG1 and the subsequent production of inflammatory cytokines by skeletal muscle, contributing to age‐related deterioration of muscle function.An in vitro model of oxidative DNA damage was established by treating C2C12 myoblasts with H2O2. DNA damage repair responses including 8‐oxoG, OGG1, PARP‐1, NF‐kB activation and cytokine/chemokine gene expression and release by muscle cells were determined using Luminex multiplex analysis. The effect of TH5487 (5µM), a selective OGG1 inhibitor on NF‐kB activation and cytokine/chemokine production was determined. The role of OGG1 in the chronic production of cytokines/chemokines by isolated muscle fibres of adult mice treated with H2O2 and of old mice was examined. Cell viability was maintained in myoblasts treated with 50µM H2O2 but Ogg1 mRNA levels were significantly increased as was acetylation of OGG1, PARP‐1 and cleaved PARP‐1 protein levels. Activation of NF‐κB was evident and accompanied by an increased expression and release of a number of cytokines/chemokines (3.7 fold, 4.2 fold, 3 fold increases in IL‐6 TNF‐a and CXCL1 mRNA respectively). The H2O2‐mediated increase in NF‐kB activation and increase in cytokine/chemokine mRNA levels were normalized when cells were pre‐treated with TH5487 prior to treatment with H2O2. Experiments using isolated muscle fibers from adult mice demonstrated an increase in NF‐κB activation following treatment with H2O2. This H2O2‐mediated increase in NF‐kB DNA binding activity was significantly decreased in muscle fibers pre‐treated with TH5487. Isolated muscle fibers from old compared with adult mice showed an increase in cytokine/chemokine release which was also reduced by treatment with TH5487. Increases in IL‐6, CCL2,CXCL1,CCL7,CCL27,CXCL5,CCL11,CXCL16 and CXCL‐12 were seen in the media of fibers from adult mice following treatment with H2O2 and most of these were then decreased to normal values by pre‐treatment with TH5487. Isolated muscle fibers from old mice showed a significant increase in IL‐6, CXCL1,CCL2,CCL7, of which all were reduced following treatment with TH5487, suggesting that activation of the OGG1 pathway may be responsible, at least in part for the increased production of cytokines/chemokines by muscle of old mice. Data on proteomic and mRNA analyses of muscles from adult and old mice for evidence of changes in DNA repair pathways with age will also be presented. A computationalmodel of DNA damage repair is being designed to identify DNA damage repair process therapeutic targets to modify activation of NF‐κB in muscles of old mice.

Oxidative stress and endogenous DNA damage in blood mononuclear cells may predict anti-SARS-CoV-2 antibody titers after vaccination in older adults

Immune senescence in the elderly has been associated with chronic oxidative stress and DNA damage accumulation. Herein we tested the hypothesis that increased endogenous DNA damage and oxidative stress in peripheral blood mononuclear cells of older adults associate with diminished humoral immune response to SARS-CoV-2 vaccination. Increased oxidative stress and DNA double-strand breaks (DSBs) were detected in 9 non-immunocompromised individuals aged 80–96 years compared to 11 adults aged 27–44 years, before, as well as on days 1 and 14 after the first dose, and on day 14 after the second dose of the BNT162B2-mRNA vaccine (all p < 0.05). SARS-CoV-2 vaccination induced a resolvable increase in oxidative stress and DNA damage, but individual DSB-repair efficiency was unaffected by vaccination irrespective of age, confirming vaccination safety. Individual titers of anti-Spike-Receptor Binding Domain (S-RBD)-IgG antibodies, and the neutralizing capacity of circulating anti-SARS-CoV-2 antibodies, measured on day 14 after the second dose in all participants, correlated inversely with the corresponding pre-vaccination endogenous oxidative stress and DSB levels (all p < 0.05). In particular, a strong inverse correlation of individual pre-vaccination DSB levels with both the respective anti-S-RBD-IgG antibodies titers (r = −0.867) and neutralizing capacity of circulating anti-SARS-CoV-2 antibodies (r = −0.983) among the 9 older adults was evident. These findings suggest that humoral responses to SARS-CoV-2 vaccination may be weaker when immune cells are under oxidative and/or genomic stress. Whether such measurements may serve as biomarkers of vaccine efficacy in older adults warrants further studies.

Abstract P1-04-09: Essential role for MUC1-C in chronic activation of cytosolic nucleotide sensing and the type I interferon pathway in triple-negative breast cancer

Abstract The MUC1-C transmembrane protein, which is aberrantly expressed in triple-negative breast cancer (TNBC), evolved in mammals to provide protection of epithelia from the external environment. MUC1-C functions as an effector of epithelial cell responses to inflammation and damage. MUC1-C induces inflammatory, proliferative and remodeling signaling pathways that are associated with wound healing. However, in contrast, prolonged MUC1-C activation in settings of chronic inflammation promotes cancer progression. Recent work has demonstrated that MUC1-C drives intrinsic activation of inflammatory signaling pathways in TNBC cells that are linked to immune evasion and oncogenesis (Yamashita N, JITC, 2021). By extension, what is needed now is a better understanding of how MUC1-C specifically integrates inflammation with TNBC progression. In addressing this issue, the present work uncovers a previously unrecognized MUC1-C activated inflammatory pathway that contributes to genomic instability and DNA damage tolerance in TNBC cells. Constitutive expression of pattern-recognition receptors (PRRs), which include the retinoic acid-inducible gene-1 (RIG-I/DDX58) and melanoma differentiation-associated gene 5 (MDA5/IFIH1), are activated by the presence of cytosolic dsRNA. Accumulation of DNA damage-associated molecular patterns (DAMPs) in the cytosol is recognized by activation of the cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Stimulation of these RNA and DNA PRRs induces production of the type I IFNs and induction of interferon-stimulated genes (ISGs) that confer DNA damage resistance. We report here that MUC1-C is necessary for constitutive activation of RIG-I, MDA5, cGAS and STING in BRCA wild type and mutant TNBC cells. Consistent with these findings, we show that MUC1-C is necessary for expression of the downstream STAT1, STAT2 and IRF9 effectors in activation of the type I IFN pathway and the IFN-related DNA damage resistance gene signature (IRDS). One of the MUC1-C-induced IRDS genes encodes ISG15, a ubiquitin-like protein that links chronic inflammation and DNA damage resistance. Of translational significance, studies in TNBC cells treated with carboplatin or the PARP inhibitor olaparib demonstrate that MUC1-C is necessary for expression of RIG-I, MDA5, cGAS, STING and ISG15 and that targeting MUC1-C abrogates this response. In addition, we show that MUC1 significantly associates with the upregulation of STING, STAT1, STAT2, IRF9 and ISG15 in TNBC tumors. In summary, these findings in TNBC uncover an essential role for MUC1-C in chronic activation of the PRR/STING axis, type I IFN pathway and IRDS in association with conferring resistance to replicative stress. Our findings also support MUC1-C as a target for inhibiting DNA damage tolerance and synergistically sensitizing BRCA wild type and mutant TNBC cells to platinum-based agents and olaparib. Citation Format: Nami Yamashita, Atsushi Fushimi, Yoshihiro Morimoto, Atrayee Bhattacharya, Mark Long, Song Liu, Donald Kufe. Essential role for MUC1-C in chronic activation of cytosolic nucleotide sensing and the type I interferon pathway in triple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-04-09.

Dietary Polyphenols and Their Role in Oxidative Stress-Induced Human Diseases: Insights Into Protective Effects, Antioxidant Potentials and Mechanism(s) of Action.

Dietary polyphenols including phenolic acids, flavonoids, catechins, tannins, lignans, stilbenes, and anthocyanidins are widely found in grains, cereals, pulses, vegetables, spices, fruits, chocolates, and beverages like fruit juices, tea, coffee and wine. In recent years, dietary polyphenols have gained significant interest among researchers due to their potential chemopreventive/protective functions in the maintenance of human health and diseases. It is believed that dietary polyphenols/flavonoids exert powerful antioxidant action for protection against reactive oxygen species (ROS)/cellular oxidative stress (OS) towards the prevention of OS-related pathological conditions or diseases. Pre-clinical and clinical evidence strongly suggest that long term consumption of diets rich in polyphenols offer protection against the development of various chronic diseases such as neurodegenerative diseases, cardiovascular diseases (CVDs), cancer, diabetes, inflammatory disorders and infectious illness. Increased intake of foods containing polyphenols (for example, quercetin, epigallocatechin-3-gallate, resveratrol, cyanidin etc.) has been claimed to reduce the extent of a majority of chronic oxidative cellular damage, DNA damage, tissue inflammations, viral/bacterial infections, and neurodegenerative diseases. It has been suggested that the antioxidant activity of dietary polyphenols plays a pivotal role in the prevention of OS-induced human diseases. In this narrative review, the biological/pharmacological significance of dietary polyphenols in the prevention of and/or protection against OS-induced major human diseases such as cancers, neurodegenerative diseases, CVDs, diabetes mellitus, cancer, inflammatory disorders and infectious diseases have been delineated. This review specifically focuses a current understanding on the dietary sources of polyphenols and their protective effects including mechanisms of action against various major human diseases.

DNA Damage and Radiosensitivity in Blood Cells from Subjects Undergoing 45 Days of Isolation and Confinement: An Explorative Study.

The effect of confined and isolated experience on astronauts’ health is an important factor to consider for future space exploration missions. The more confined and isolated humans are, the more likely they are to develop negative behavioral or cognitive conditions such as a mood decline, sleep disorder, depression, fatigue and/or physiological problems associated with chronic stress. Molecular mediators of chronic stress, such as cytokines, stress hormones or reactive oxygen species (ROS) are known to induce cellular damage including damage to the DNA. In view of the growing evidence of chronic stress-induced DNA damage, we conducted an explorative study and measured DNA strand breaks in 20 healthy adults. The participants were grouped into five teams (missions). Each team was composed of four participants, who spent 45 days in isolation and confinement in NASA’s Human Exploration Research Analog (HERA). Endogenous DNA integrity, ex-vivo radiation-induced DNA damage and the rates of DNA repair were assessed every week. Our results show a high inter-individual variability as well as differences between the missions, which cannot be explained by inter-individual variability alone. The ages and sex of the participants did not appear to influence the results.