Alterations in gene expression profiles and the DNA-damage response in ionizing radiation-exposed TK6 cells

2005 ◽  
Vol 45 (2-3) ◽  
pp. 188-205 ◽  
Author(s):  
Gregory S. Akerman ◽  
Barry A. Rosenzweig ◽  
Olen E. Domon ◽  
Chen-An Tsai ◽  
Michelle E. Bishop ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Ionizing Radiation ◽  
Dna Damage Response ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Damage Response ◽  
Tk6 Cells

scholarly journals LINCS gene expression signatures analysis revealed bosutinib as a radiosensitizer of breast cancer cells by targeting eIF4G1

2020 ◽  
Author(s):  
Sai Hu ◽  
Pingkun Zhou ◽  
Xiaodan Liu ◽  
Xiaoyao Yin ◽  
Dafei Xie ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Dna Damage ◽  
Ionizing Radiation ◽  
Cancer Cells ◽  
Dna Damage Response ◽  
Breast Cancer Cells ◽  
Potential Candidate ◽  
Damage Response ◽  
Gene Expression Signatures

AbstractRadioresistance represents the predominant cause for radiotherapy failure and disease progression, resulting in increased breast cancer mortality. Through gene expression signatures analyses of Library of Integrated Network-Based Cellular Signatures (LINCS) and Gene Expression Omnibus (GEO), the present study aimed to identify potential candidate radiosensitizers from known drugs systematically. The similarity of integrated gene expression signatures between irradiated eIF4G1-silenced breast cancer cells and known drugs was measured by enrichment scores. Drugs with positive enrichment scores were selected as potential radiosensitizers. The radiosensitizing effects of the candidate radiosensitizers were analyzed in breast cancer cells (MCF-7, MX-1, and MDA-MB-231) by CCK-8 assays and colony-forming capability after exposure to ionizing radiation. Cell apoptosis was detected by flow cytometry. Expressions of eIF4G1 and a series of DNA damage response proteins were analyzed by Western blot assays. Bosutinib was proposed to be a promising radiosensitizer as its administration markedly reduced the dosages of both the drug and ionizing radiation and was associated with fewer adverse drug reactions. The combined treatment with ionizing radiation and bosutinib significantly increased the cells killing potency in all three cell lines as compared to ionizing radiation or bosutinib alone. MX-1 cells were revealed to be the most sensitive to both ionizing radiation and bosutinib among the three cell lines. Bosutinib noticeably downregulated the expression of eIF4G1 in a dose-dependent manner and also reduced the expression of DNA damage response proteins (including ATM, XRCC4, ATRIP, and GADD45a). Moreover, eIF4G1 could be a key target of bosutinib through which it regulates DNA damage induced by ionizing radiation. Thus, taken together, bosutinib may serve as a potential candidate radiosensitizer for breast cancer therapy.

scholarly journals TCF19 Impacts a Network of Inflammatory and DNA Damage Response Genes in the Pancreatic β-Cell

Metabolites ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 513
Author(s):  
Grace H. Yang ◽  
Danielle A. Fontaine ◽  
Sukanya Lodh ◽  
Joseph T. Blumer ◽  
Avtar Roopra ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Association Studies ◽  
Cell Cycle Gene ◽  
Genome Wide Association Studies ◽  
Β Cell ◽  
Nucleotide Incorporation ◽  
Damage Response ◽  
The Impact

Transcription factor 19 (TCF19) is a gene associated with type 1 diabetes (T1DM) and type 2 diabetes (T2DM) in genome-wide association studies. Prior studies have demonstrated that Tcf19 knockdown impairs β-cell proliferation and increases apoptosis. However, little is known about its role in diabetes pathogenesis or the effects of TCF19 gain-of-function. The aim of this study was to examine the impact of TCF19 overexpression in INS-1 β-cells and human islets on proliferation and gene expression. With TCF19 overexpression, there was an increase in nucleotide incorporation without any change in cell cycle gene expression, alluding to an alternate process of nucleotide incorporation. Analysis of RNA-seq of TCF19 overexpressing cells revealed increased expression of several DNA damage response (DDR) genes, as well as a tightly linked set of genes involved in viral responses, immune system processes, and inflammation. This connectivity between DNA damage and inflammatory gene expression has not been well studied in the β-cell and suggests a novel role for TCF19 in regulating these pathways. Future studies determining how TCF19 may modulate these pathways can provide potential targets for improving β-cell survival.

Dissecting the Role of Thyrotropin in the DNA Damage Response in Human Thyrocytes after 131I, γ Radiation and H2O2

2019 ◽  
Vol 105 (3) ◽  
pp. 839-853
Author(s):  
Aglaia Kyrilli ◽  
David Gacquer ◽  
Vincent Detours ◽  
Anne Lefort ◽  
Frédéric Libert ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Iodide Uptake ◽  
Transcriptomic Response ◽  
Uptake Inhibition ◽  
Γ Radiation ◽  
Damage Response

Abstract Background The early molecular events in human thyrocytes after 131I exposure have not yet been unravelled. Therefore, we investigated the role of TSH in the 131I-induced DNA damage response and gene expression in primary cultured human thyrocytes. Methods Following exposure of thyrocytes, in the presence or absence of TSH, to 131I (β radiation), γ radiation (3 Gy), and hydrogen peroxide (H2O2), we assessed DNA damage, proliferation, and cell-cycle status. We conducted RNA sequencing to profile gene expression after each type of exposure and evaluated the influence of TSH on each transcriptomic response. Results Overall, the thyrocyte responses following exposure to β or γ radiation and to H2O2 were similar. However, TSH increased 131I-induced DNA damage, an effect partially diminished after iodide uptake inhibition. Specifically, TSH increased the number of DNA double-strand breaks in nonexposed thyrocytes and thus predisposed them to greater damage following 131I exposure. This effect most likely occurred via Gα q cascade and a rise in intracellular reactive oxygen species (ROS) levels. β and γ radiation prolonged thyroid cell-cycle arrest to a similar extent without sign of apoptosis. The gene expression profiles of thyrocytes exposed to β/γ radiation or H2O2 were overlapping. Modulations in genes involved in inflammatory response, apoptosis, and proliferation were observed. TSH increased the number and intensity of modulation of differentially expressed genes after 131I exposure. Conclusions TSH specifically increased 131I-induced DNA damage probably via a rise in ROS levels and produced a more prominent transcriptomic response after exposure to 131I.

Characterization of gene expression profiles at low and very low doses of ionizing radiation

DNA Repair ◽  
2013 ◽  
Vol 12 (7) ◽  
pp. 508-517 ◽  
Author(s):  
Ingrid Nosel ◽  
Aurélie Vaurijoux ◽  
Joan-Francesc Barquinero ◽  
Gaetan Gruel
Keyword(s):  
Gene Expression ◽  
Ionizing Radiation ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Low Doses

Pseudorabies virus infection triggers NF-κB activation via the DNA damage response, but actively inhibits NFkB-dependent gene expression

2021 ◽  
Author(s):  
Nicolás Romero ◽  
Herman W. Favoreel
Keyword(s):  
Gene Expression ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Pseudorabies Virus ◽  
Critical Role ◽  
Genome Replication ◽  
Viral Protein Synthesis ◽  
Damage Response ◽  
Signaling Axis ◽  
Inside Out

The nuclear factor kappa B (NF-κB) pathway is known to integrate signaling associated with very diverse intra- and extracellular stressors including virus infections, and triggers a powerful (pro-inflammatory) response through the expression of NF-κB-regulated genes. Typically, the NF-κB pathway collects and transduces threatening signals at the cell surface or in the cytoplasm leading to nuclear import of activated NF-κB transcription factors. In the current work, we demonstrate that the swine alphaherpesvirus pseudorabies virus (PRV) induces a peculiar mode of NF-κB activation known as “inside-out” NF-κB activation. We show that PRV triggers the DNA damage response (DDR) and that this DDR response drives NF-κB activation since inhibition of the nuclear ataxia telangiectasia-mutated (ATM) kinase, a chief controller of DDR, abolished PRV-induced NF-κB activation. Initiation of the DDR-NF-κB signaling axis requires viral protein synthesis but occurs before active viral genome replication. In addition, the initiation of the DDR-NF-κB signaling axis is followed by a virus-induced complete shutoff of NF-κB-dependent gene expression that depends on viral DNA replication. In summary, the results presented in this study reveal that PRV infection triggers a non-canonical DDR-NF-κB activation signaling axis and that the virus actively inhibits the (potentially antiviral) consequences of this pathway, by inhibiting NF-κB-dependent gene expression. IMPORTANCE: The NF-κB signaling pathway plays a critical role in coordination of innate immune responses that are of vital importance in the control of infections. The current report generates new insights in the interaction of the alphaherpesvirus pseudorabies virus (PRV) with the NF-κB pathway, as they reveal that (i) PRV infection leads to NF-κB activation via a peculiar “inside-out’ nucleus-to-cytoplasm signal that is triggered via the DNA damage response (DDR), (ii) the DDR-NF-κB signaling axis requires expression of viral proteins but is initiated before active PRV replication, and (iii) late viral factor(s) allow PRV to actively and efficiently inhibit NF-κB-dependent (pro-inflammatory) gene expression. These data suggest that activation of the DDR-NF-κB during PRV infection is host-driven and that its potential antiviral consequences are actively inhibited by the virus.

scholarly journals Differential DNA Damage Response of Peripheral Blood Lymphocyte Populations

2021 ◽  
Vol 12 ◽  
Author(s):  
Kerstin Felgentreff ◽  
Catharina Schuetz ◽  
Ulrich Baumann ◽  
Christian Klemann ◽  
Dorothee Viemann ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Ionizing Radiation ◽  
Dna Damage Response ◽  
Peripheral Blood ◽  
Low Dose ◽  
Lymphocyte Subsets ◽  
Mass Cytometry ◽  
Damage Response ◽  
Lymphocyte Populations

DNA damage occurs constantly in every cell triggered by endogenous processes of replication and metabolism, and external influences such as ionizing radiation and intercalating chemicals. Large sets of proteins are involved in sensing, stabilizing and repairing this damage including control of cell cycle and proliferation. Some of these factors are phosphorylated upon activation and can be used as biomarkers of DNA damage response (DDR) by flow and mass cytometry. Differential survival rates of lymphocyte subsets in response to DNA damage are well established, characterizing NK cells as most resistant and B cells as most sensitive to DNA damage. We investigated DDR to low dose gamma radiation (2Gy) in peripheral blood lymphocytes of 26 healthy donors and 3 patients with ataxia telangiectasia (AT) using mass cytometry. γH2AX, p-CHK2, p-ATM and p53 were analyzed as specific DDR biomarkers for functional readouts of DNA repair efficiency in combination with cell cycle and T, B and NK cell populations characterized by 20 surface markers. We identified significant differences in DDR among lymphocyte populations in healthy individuals. Whereas CD56+CD16+ NK cells showed a strong γH2AX response to low dose ionizing radiation, a reduced response rate could be observed in CD19+CD20+ B cells that was associated with reduced survival. Interestingly, γH2AX induction level correlated inversely with ATM-dependent p-CHK2 and p53 responses. Differential DDR could be further noticed in naïve compared to memory T and B cell subsets, characterized by reduced γH2AX, but increased p53 induction in naïve T cells. In contrast, DDR was abrogated in all lymphocyte populations of AT patients. Our results demonstrate differential DDR capacities in lymphocyte subsets that depend on maturation and correlate inversely with DNA damage-related survival. Importantly, DDR analysis of peripheral blood cells for diagnostic purposes should be stratified to lymphocyte subsets.

scholarly journals Inhibition of mutant PPM1D enhances DNA damage response and growth suppressive effects of ionizing radiation in diffuse intrinsic pontine glioma

2019 ◽  
Vol 21 (6) ◽  
pp. 786-799 ◽  
Author(s):  
Mwangala Precious Akamandisa ◽  
Kai Nie ◽  
Rita Nahta ◽  
Dolores Hambardzumyan ◽  
Robert Craig Castellino
Keyword(s):  
Dna Damage ◽  
Ionizing Radiation ◽  
Dna Damage Response ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Pontine Glioma ◽  
Damage Response

scholarly journals Analysis of DNA-damage response to ionizing radiation in serum-shock synchronized human fibroblasts

2017 ◽  
Vol 33 (4) ◽  
pp. 373-388 ◽  
Author(s):  
Samantha Corrà ◽  
Riccardo Salvadori ◽  
Leonardo Bee ◽  
Vito Barbieri ◽  
Maddalena Mognato
Keyword(s):  
Dna Damage ◽  
Ionizing Radiation ◽  
Dna Damage Response ◽  
Human Fibroblasts ◽  
Damage Response
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