The Translationally Controlled Tumor Protein and the Cellular Response to Ionizing Radiation-Induced DNA Damage

2017 ◽  
pp. 227-253 ◽  
Author(s):  
Jie Zhang ◽  
Grace Shim ◽  
Sonia M. de Toledo ◽  
Edouard I. Azzam
Keyword(s):  
Dna Damage ◽  
Ionizing Radiation ◽  
Cellular Response ◽  
Translationally Controlled Tumor Protein ◽  
Radiation Induced

scholarly journals DNA Damage Caused by Ionizing Radiation in Embryonic Diploid Fibroblasts WI-38 Induces Both Apoptosis and Senescence

2011 ◽  
pp. 667-677 ◽  
Author(s):  
J. CMIELOVÁ ◽  
R. HAVELEK ◽  
A. JIROUTOVÁ ◽  
R. KOHLEROVÁ ◽  
M. SEIFRTOVÁ ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Ionizing Radiation ◽  
Cellular Response ◽  
Diploid Fibroblasts ◽  
Cycle Arrest ◽  
Permanent Cell ◽  
Radiation Induced ◽  
G2 Phase ◽  
Stress Induced Premature Senescence

Cellular response to ionizing radiation-induced damage depends on the cell type and the ability to repair DNA damage. Some types of cells undergo apoptosis, whereas others induce a permanent cell cycle arrest and do not proliferate. Our study demonstrates two types of response of embryonic diploid fibroblasts WI-38 to ionizing radiation. In the WI-38 cells p53 is activated, protein p21 increases, but the cells are arrested in G2 phase of cell cycle. Some of the cells die by apoptosis, but in remaining viable cells p16 increases, senescence associated DNA-damage foci occur, and senescence-associated beta-galactosidase activity increases, which indicate stress-induced premature senescence.

scholarly journals Truncated PPM1D Prevents Apoptosis in the Murine Thymus and Promotes Ionizing Radiation-Induced Lymphoma

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2068
Author(s):  
Andra S. Martinikova ◽  
Monika Burocziova ◽  
Miroslav Stoyanov ◽  
Libor Macurek
Keyword(s):  
Dna Damage ◽  
Ionizing Radiation ◽  
Tumor Formation ◽  
Cell Cycle Checkpoints ◽  
Negative Regulator ◽  
Tumor Suppressor P53 ◽  
Mouse Thymus ◽  
Truncating Mutation ◽  
T Cell Lymphomas ◽  
Radiation Induced

Genome integrity is protected by the cell-cycle checkpoints that prevent cell proliferation in the presence of DNA damage and allow time for DNA repair. The transient checkpoint arrest together with cellular senescence represent an intrinsic barrier to tumorigenesis. Tumor suppressor p53 is an integral part of the checkpoints and its inactivating mutations promote cancer growth. Protein phosphatase magnesium-dependent 1 (PPM1D) is a negative regulator of p53. Although its loss impairs recovery from the G2 checkpoint and promotes induction of senescence, amplification of the PPM1D locus or gain-of-function truncating mutations of PPM1D occur in various cancers. Here we used a transgenic mouse model carrying a truncating mutation in exon 6 of PPM1D (Ppm1dT). As with human cell lines, we found that the truncated PPM1D was present at high levels in the mouse thymus. Truncated PPM1D did not affect differentiation of T-cells in the thymus but it impaired their response to ionizing radiation (IR). Thymocytes in Ppm1dT/+ mice did not arrest in the checkpoint and continued to proliferate despite the presence of DNA damage. In addition, we observed a decreased level of apoptosis in the thymi of Ppm1dT/+ mice. Moreover, the frequency of the IR-induced T-cell lymphomas increased in Ppm1dT/+Trp53+/− mice resulting in decreased survival. We conclude that truncated PPM1D partially suppresses the p53 pathway in the mouse thymus and potentiates tumor formation under the condition of a partial loss of p53 function.

scholarly journals Veliparib Is an Effective Radiosensitizing Agent in a Preclinical Model of Medulloblastoma

2021 ◽  
Vol 8 ◽  
Author(s):  
Jessica Buck ◽  
Patrick J. C. Dyer ◽  
Hilary Hii ◽  
Brooke Carline ◽  
Mani Kuchibhotla ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Combination Therapy ◽  
Cellular Response ◽  
Molecular Subtype ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Parp Inhibition ◽  
Preclinical Model ◽  
Radiation Induced

Medulloblastoma is the most common malignant childhood brain tumor, and 5-year overall survival rates are as low as 40% depending on molecular subtype, with new therapies critically important. As radiotherapy and chemotherapy act through the induction of DNA damage, the sensitization of cancer cells through the inhibition of DNA damage repair pathways is a potential therapeutic strategy. The poly-(ADP-ribose) polymerase (PARP) inhibitor veliparib was assessed for its ability to augment the cellular response to radiation-induced DNA damage in human medulloblastoma cells. DNA repair following irradiation was assessed using the alkaline comet assay, with veliparib inhibiting the rate of DNA repair. Veliparib treatment also increased the number of γH2AX foci in cells treated with radiation, and analysis of downstream pathways indicated persistent activation of the DNA damage response pathway. Clonogenicity assays demonstrated that veliparib effectively inhibited the colony-forming capacity of medulloblastoma cells, both as a single agent and in combination with irradiation. These data were then validated in vivo using an orthotopic implant model of medulloblastoma. Mice harboring intracranial D425 medulloblastoma xenografts were treated with vehicle, veliparib, 18 Gy multifractionated craniospinal irradiation (CSI), or veliparib combined with 18 Gy CSI. Animals treated with combination therapy exhibited reduced tumor growth rates concomitant with increased intra-tumoral apoptosis observed by immunohistochemistry. Kaplan–Meier analyses revealed a statistically significant increase in survival with combination therapy compared to CSI alone. In summary, PARP inhibition enhanced radiation-induced cytotoxicity of medulloblastoma cells; thus, veliparib or other brain-penetrant PARP inhibitors are potential radiosensitizing agents for the treatment of medulloblastoma.

Irreversible electron attachment – a key to DNA damage by solvated electrons in aqueous solution

2015 ◽  
Vol 13 (41) ◽  
pp. 10362-10369 ◽  
Author(s):  
K. Westphal ◽  
J. Wiczk ◽  
J. Miloch ◽  
G. Kciuk ◽  
K. Bobrowski ◽  
...  
Keyword(s):  
Aqueous Solution ◽  
Dna Damage ◽  
Ionizing Radiation ◽  
Electron Attachment ◽  
Solvated Electrons ◽  
Radiation Induced

In an aqueous solution trinucleotides labeled with bromonucleobases are damaged by ionizing radiation induced electrons while native trimers are insensitive to electrons under the same conditions.

Analysis of ionizing radiation-induced foci of DNA damage repair proteins

2005 ◽  
Vol 574 (1-2) ◽  
pp. 22-33 ◽  
Author(s):  
Lieneke R. van Veelen ◽  
Tiziana Cervelli ◽  
Mandy W.M.M. van de Rakt ◽  
Arjan F. Theil ◽  
Jeroen Essers ◽  
...  
Keyword(s):  
Dna Damage ◽  
Ionizing Radiation ◽  
Dna Damage Repair ◽  
Damage Repair ◽  
Radiation Induced

Modification of radiation-induced apoptosis in radiation- or hyperthermia-adapted human lymphocytes

1994 ◽  
Vol 72 (11-12) ◽  
pp. 475-482 ◽  
Author(s):  
S. P. Cregan ◽  
D. R. Boreham ◽  
P. R. Walker ◽  
D. L. Brown ◽  
R. E. J. Mitchel
Keyword(s):  
Dna Damage ◽  
Ionizing Radiation ◽  
Adaptive Response ◽  
Human Peripheral Blood ◽  
Human Lymphocytes ◽  
Fluorescence Analysis ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Protective Mechanism ◽  
Radiation Induced ◽  
Induced Apoptosis

We have investigated the influence of the cellular adaptive response to ionizing radiation on radiation-induced apoptosis in human cells. The adaptive response is believed to be a protective mechanism that confers resistance to the detrimental effects of ionizing radiation and that can be induced by different agents, including hyperthermia and radiation. We have used fluorescence analysis of DNA unwinding (FADU) to assay the induction of apoptosis in human peripheral blood lymphocytes by ionizing radiation. Using the FADU assay, we have observed the initial radiation-induced DNA damage, its subsequent disappearance due to enzymatic repair, and its time- and dose-dependent reappearance. We believe this reappearance of DNA damage to be indicative of the DNA fragmentation event associated with apoptosis. This interpretation has been supported at the individual cell level using an in situ terminal deoxynucleotidyl transferase (TDT) assay (Apoptag, Oncor Inc.), which detects the 3′-hydroxyl ends of fragmented DNA, and by fluorescence analysis of nuclear morphology in Hoechst 33258 stained cells. Pretreatment of cells with low-dose γ-radiation (0.1 Gy) or mild hyperthermia (40 °C for 30 min) altered the extent of radiation-induced (3 Gy) apoptosis. Both pretreatments sensitized lymphocytes to become apoptotic after the 3-Gy radiation exposure. This sensitization may represent an adaptive response mechanism that reduces the risk that genetically damaged cells will proliferate. The ability to modify the probability of radiation-induced apoptosis may lower the cancer risk from a radiation exposure.Key words: apoptosis, adaptive response, ionizing radiation, hyperthermia.

Ionizing radiation induced signaling of DNA damage response molecules in RAW 264.7 and CD4+ T cells

2011 ◽  
Vol 363 (1-2) ◽  
pp. 43-51 ◽  
Author(s):  
Fatema A. Dhariwala ◽  
Himanshi Narang ◽  
Malini Krishna
Keyword(s):  
Dna Damage ◽  
T Cells ◽  
Ionizing Radiation ◽  
Dna Damage Response ◽  
Cd4 T Cells ◽  
Raw 264.7 ◽  
Damage Response ◽  
Radiation Induced
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