scholarly journals Hyperthermia Activates a Subset of Ataxia-Telangiectasia Mutated Effectors Independent of DNA Strand Breaks and Heat Shock Protein 70 Status

2007 ◽  
Vol 67 (7) ◽  
pp. 3010-3017 ◽  
Author(s):  
Clayton R. Hunt ◽  
Raj K. Pandita ◽  
Andrei Laszlo ◽  
Ryuji Higashikubo ◽  
Manjula Agarwal ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Ataxia Telangiectasia ◽  
Heat Shock Protein 70 ◽  
Dna Strand Breaks ◽  
Ataxia Telangiectasia Mutated ◽  
Strand Breaks ◽  
Dna Strand

scholarly journals Long-term exposure to a 40-GHz electromagnetic field does not affect genotoxicity or heat shock protein expression in HCE-T or SRA01/04 cells

2019 ◽  
Vol 60 (4) ◽  
pp. 417-423 ◽  
Author(s):  
Shin Koyama ◽  
Eijiro Narita ◽  
Yukihisa Suzuki ◽  
Takeo Shiina ◽  
Masao Taki ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Protein Expression ◽  
Millimeter Waves ◽  
Dna Strand Breaks ◽  
Human Lens ◽  
Corneal Epithelial ◽  
Strand Breaks ◽  
Heat Shock Protein Expression ◽  
Dna Strand

AbstractMillimeter waves are used in various fields, and the risks of this wavelength range for human health must be carefully evaluated. In this study, we investigated the effects of millimeter waves on genotoxicity and heat shock protein expression in human corneal epithelial (HCE-T) and human lens epithelial (SRA01/04) cells. We exposed the cells to 40-GHz millimeter waves at 1 mW/cm2 for 24 h. We observed no statistically significant increase in the micronucleus (MN) frequency or the level of DNA strand breaks in cells exposed to 40-GHz millimeter waves relative to sham-exposed and incubator controls. Heat shock protein (Hsp) expression also exhibited no statistically significant response to the 40-GHz exposure. These results indicate that exposure to 40 GHz millimeter waves under these conditions has little or no effect on MN formation, DNA strand breaks, or Hsp expression in HCE-T or SRA01/04 cells.

Methotrexate-induced morphological changes mimic those seen after heat shock

1989 ◽  
Vol 92 (1) ◽  
pp. 37-49
Author(s):  
D.A. Jackson ◽  
C.K. Pearson ◽  
D.C. Fraser ◽  
K.M. Prise ◽  
S.Y. Wong
Keyword(s):  
Heat Shock ◽  
Morphological Changes ◽  
Dna Strand Breaks ◽  
Chemotherapeutic Drug ◽  
General Stress Response ◽  
Strand Breaks ◽  
Nucleotide Pools ◽  
Concentration Changes ◽  
High Concentrations ◽  
Dna Strand

The survival of cells cultured in medium containing the chemotherapeutic drug methotrexate (MTX) is related directly to drug concentration. Changes in DNA resulting from a severe imbalance in the cells' nucleotide pools are thought to account for this cytotoxicity. We have attempted to clarify the gross biochemical changes that might lead to cell death. DNA strand breaks occur in cells treated with high concentrations of MTX but it is not clear that these are sufficient to account for cytotoxicity at lower doses. We observed dramatic changes in cytoskeletal morphology. Gross reorganization of the cytoskeleton is shown by immunolabelling but is high-lighted dramatically when cells are lysed to leave ‘nucleoids’. The nature of the changes seen in MTX-treated cells is characteristic of the cells’ general stress response, seen originally following heat shock. This study shows that other factors, such as changes in cytoskeletal function, must be considered together with any contribution from DNA damage, in order to account for the lethal effects of MTX.

scholarly journals Inhibition of replicon initiation in human cells following stabilization of topoisomerase-DNA cleavable complexes.

1991 ◽  
Vol 11 (7) ◽  
pp. 3711-3718 ◽  
Author(s):  
W K Kaufmann ◽  
J C Boyer ◽  
L L Estabrooks ◽  
S J Wilson
Keyword(s):  
Ataxia Telangiectasia ◽  
Topoisomerase I ◽  
Cellular Response ◽  
Human Fibroblasts ◽  
Dna Strand Breaks ◽  
Velocity Sedimentation ◽  
Type I ◽  
Dna Topoisomerase ◽  
Strand Breaks ◽  
Dna Strand

Diploid human fibroblast strains were treated for 10 min with inhibitors of type I and type II DNA topoisomerases, and after removal of the inhibitors, the rate of initiation of DNA synthesis at replicon origins was determined. By alkaline elution chromatography, 4'-(9-acridinylamino)methanesulfon-m-anisidide (amsacrine), an inhibitor of DNA topoisomerase II, was shown to produce DNA strand breaks. These strand breaks are thought to reflect drug-induced stabilization of topoisomerase-DNA cleavable complexes. Removal of the drug led to a rapid resealing of the strand breaks by dissociation of the complexes. Velocity sedimentation analysis was used to quantify the effects of amsacrine treatment on DNA replication. It was demonstrated that transient exposure to low concentrations of amsacrine inhibited replicon initiation but did not substantially affect DNA chainelongation within operating replicons. Maximal inhibition of replicon initiation occurred 20 to 30 min after drug treatment, and the initiation rate recovered 30 to 90 min later. Ataxia telangiectasia cells displayed normal levels of amsacrine-induced DNA strand breaks during stabilization of cleavable complexes but failed to downregulate replicon initiation after exposure to the topoisomerase inhibitor. Thus, inhibition of replicon initiation in response to DNA damage appears to be an active process which requires a gene product which is defective or missing in ataxia telangiectasia cells. In normal human fibroblasts, the inhibition of DNA topoisomerase I by camptothecin produced reversible DNA strand breaks. Transient exposure to this drug also inhibited replicon initiation. These results suggest that the cellular response pathway which downregulates replicon initiation following genotoxic damage may respond to perturbations of chromatin structure which accompany stabilization of topoisomerase-DNA cleavable complexes.

Normal Rejoining of DNA Strand Breaks in Ataxia Telangiectasia Fibroblast Lines after Low X-Ray Exposure

1981 ◽  
Vol 86 (3) ◽  
pp. 589 ◽  
Author(s):  
P. V. Hariharan ◽  
S. Eleczko ◽  
B. P. Smith ◽  
M. C. Paterson
Keyword(s):  
Ataxia Telangiectasia ◽  
Dna Strand Breaks ◽  
Strand Breaks ◽  
X Ray ◽  
Dna Strand ◽  
Low X

scholarly journals Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks

2006 ◽  
Vol 173 (2) ◽  
pp. 195-206 ◽  
Author(s):  
Simon Bekker-Jensen ◽  
Claudia Lukas ◽  
Risa Kitagawa ◽  
Fredrik Melander ◽  
Michael B. Kastan ◽  
...  
Keyword(s):  
Spatial Organization ◽  
Protein A ◽  
Dna Strand Breaks ◽  
Double Strand Breaks ◽  
Dna Double Strand Breaks ◽  
Ataxia Telangiectasia Mutated ◽  
Interacting Protein ◽  
Atm Kinase ◽  
Strand Breaks ◽  
Dna Strand

We show that DNA double-strand breaks (DSBs) induce complex subcompartmentalization of genome surveillance regulators. Chromatin marked by γ-H2AX is occupied by ataxia telangiectasia–mutated (ATM) kinase, Mdc1, and 53BP1. In contrast, repair factors (Rad51, Rad52, BRCA2, and FANCD2), ATM and Rad-3–related (ATR) cascade (ATR, ATR interacting protein, and replication protein A), and the DNA clamp (Rad17 and -9) accumulate in subchromatin microcompartments delineated by single-stranded DNA (ssDNA). BRCA1 and the Mre11–Rad50–Nbs1 complex interact with both of these compartments. Importantly, some core DSB regulators do not form cytologically discernible foci. These are further subclassified to proteins that connect DSBs with the rest of the nucleus (Chk1 and -2), that assemble at unprocessed DSBs (DNA-PK/Ku70), and that exist on chromatin as preassembled complexes but become locally modified after DNA damage (Smc1/Smc3). Finally, checkpoint effectors such as p53 and Cdc25A do not accumulate at DSBs at all. We propose that subclassification of DSB regulators according to their residence sites provides a useful framework for understanding their involvement in diverse processes of genome surveillance.

scholarly journals Heat shock protein 70 regulates Tcl1 expression in leukemia and lymphomas

Blood ◽  
2013 ◽  
Vol 121 (2) ◽  
pp. 351-359 ◽  
Author(s):  
Eugenio Gaudio ◽  
Francesco Paduano ◽  
Apollinaire Ngankeu ◽  
Francesca Lovat ◽  
Muller Fabbri ◽  
...  
Keyword(s):  
T Cell ◽  
Heat Shock ◽  
Chronic Lymphocytic Leukemia ◽  
Heat Shock Protein ◽  
B Cell ◽  
Ataxia Telangiectasia ◽  
Critical Role ◽  
Lymphocytic Leukemia ◽  
Ataxia Telangiectasia Mutated ◽  
Prolymphocytic Leukemia

Abstract T-cell leukemia/lymphoma 1 (TCL1) is an oncogene overexpressed in T-cell prolymphocytic leukemia and in B-cell malignancies including B-cell chronic lymphocytic leukemia and lymphomas. To date, only a limited number of Tcl1-interacting proteins that regulate its oncogenic function have been identified. Prior studies used a proteomic approach to identify a novel interaction between Tcl1 with Ataxia Telangiectasia Mutated. The association of Tcl1 and Ataxia Telangiectasia Mutated leads to activation of the NF-κB pathway. Here, we demonstrate that Tcl1 also interacts with heat shock protein (Hsp) 70. The Tcl1-Hsp70 complex was validated by coimmunoprecipitation experiments. In addition, we report that Hsp70, a protein that plays a critical role in the folding and maturation of several oncogenic proteins, associates with Tcl1 protein and stabilizes its expression. The inhibition of the ATPase activity of Hsp70 results in ubiquitination and proteasome-dependent degradation of Tcl1. The inhibition of Hsp70 significantly reduced the growth of lymphoma xenografts in vivo and down-regulated the expression of Tcl1 protein. Our findings reveal a functional interaction between Tcl1 and Hsp70 and identify Tcl1 as a novel Hsp70 client protein. These findings suggest that inhibition of Hsp70 may represent an alternative effective therapy for chronic lymphocytic leukemia and lymphomas via its ability to inhibit the oncogenic functions of Tcl1.

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