The role of DNA double strand breaks in lonizing radiation‐induced killing of eukaryotic cells

Iliakis, George

doi:10.1002/bies.950131204

Cited by 293 publications

(132 citation statements)

References 57 publications

Supporting

Mentioning

127

Contrasting

Unclassified

Order By: Relevance

“…On average, 40 double-strand breaks per gray of radiation are induced (47), implying that 200 and 400 breaks were induced in cells after 5 and 10 Gy of X rays, respectively. DNA double-strand breaks are rapidly rejoined after radiation exposure (22,48) and are unlikely to contribute to the delayed chromosome instability observed here. It is possible that these late-appearing rearrangements result from a subset of persistent lesions passed from generation to generation.…”

Section: Methodsmentioning

confidence: 74%

Delayed chromosomal instability induced by DNA damage.

Marder¹,

Morgan²

1993

Mol. Cell. Biol.

221

View full text Add to dashboard Cite

DNA damage induced by ionizing radiation can result in gene mutation, gene amplification, chromosome rearrangements, cellular transformation, and cell death. Although many of these changes may be induced directly by the radiation, there is accumulating evidence for delayed genomic instability following X-ray exposure. We have investigated this phenomenon by studying delayed chromosomal instability in a hamsterhuman hybrid cell line by means of fluorescence in situ hybridization. We examined populations of metaphase cells several generations after expanding single-cell colonies that had survived 5 or 10 Gy of X rays. Delayed chromosomal instability, manifested as multiple rearrangements of human chromosome 4 in a background of hamster chromosomes, was observed in 29%o of colonies surviving 5 Gy and in 62% of colonies surviving 10 Gy. A correlation of delayed chromosomal instability with delayed reproductive cell death, manifested as reduced plating efficiency in surviving clones, suggests a role for chromosome rearrangements in cytotoxicity. There were small differences in chromosome destabilization and plating efficiencies between cells irradiated with 5 or

show abstract

Section: Methodsmentioning

confidence: 74%

Delayed chromosomal instability induced by DNA damage.

Marder¹,

Morgan²

1993

Mol. Cell. Biol.

221

View full text Add to dashboard Cite

show abstract

“…DNA DSBs are the primary determinant of cytotoxicity in cells treated with ionizing radiation (20). The comet assay was used to measure fragmented DNA in irradiated cells (21,22).…”

Section: Resultsmentioning

confidence: 99%

“…Cells were grown to 80% confluence on slides and pretreated with 200 nmol/L of IC87361 2 hours before irradiation with 6 Gy. Six hours later, cells were scraped, washed, and placed into a lowmelting agarose gel according to Trevigen protocol (20). Slides were then placed in an electrophoresis chamber and run for 20 minutes.…”

Section: Methodsmentioning

confidence: 99%

DNA-Dependent Protein Kinase Is a Molecular Target for the Development of Noncytotoxic Radiation–Sensitizing Drugs

et al. 2005

View full text Add to dashboard Cite

DNA-dependent protein kinase (DNA-PK)-defective severe combined immunodeficient (SCID) mice have a greater sensitivity to ionizing radiation compared with wild-type mice due to deficient repair of DNA double-strand break. SCID cells were therefore studied to determine whether radiosensitization by the specific inhibitor of DNA-PK, IC87361, is eliminated in the absence of functional DNA-PK. IC87361 enhanced radiation sensitivity in wild-type C57BL6 endothelial cells but not in SCID cells. The tumor vascular window model was used to assess IC87361-induced radiosensitization of SCID and wild-type tumor microvasculature. Vascular density was 5% in irradiated SCID host compared with 50% in C57BL6 mice (P < 0.05). IC87361 induced radiosensitization of tumor microvasculature in wild-type mice that resembled the radiosensitive phenotype of tumor vessels in SCID mice. Radiosensitization by IC87361 was eliminated in SCID tumor vasculature, which lack functional DNA-PK. Irradiated LLC and B16F0 tumors implanted into SCID mice showed greater tumor growth delay compared with tumors implanted into either wild-type C57BL6 or nude mice. Furthermore, LLC tumors treated with radiation and IC87361 showed tumor growth delay that was significantly greater than tumors treated with radiation alone (P < 0.01 for 3 Gy alone versus 3 Gy + IC87361). DNA-PK inhibitors induced no cytotoxicity and no toxicity in mouse normal tissues. Mouse models deficient in enzyme activity are useful to assess the specificity of novel kinase inhibitors. DNA-PK is an important target for the development of novel radiation-sensitizing drugs that have little intrinsic cytotoxicity. (Cancer Res 2005; 65(12): 4987-92)

show abstract

“…A large amount of evidence indicates that unrepaired or misrepaired DSBs in the DNA can lead to cell death/ apoptosis (Ward, 1988;Frankenberg-Schwager, 1989;Iliakis, 1991;McMillan and Peacock, 1994;Jeggo, 1998). The death resulting from radiation is now, to a considerable degree, understood as radiosensitivity.…”

Section: P53-mediated Apoptosis In Irmentioning

confidence: 99%

P53 and radiation responses

2003

View full text Add to dashboard Cite

Cells have evolved elaborate mechanisms (checkpoints) to monitor genomic integrity in order to ensure the highfidelity transmission of genetic information. Cells harboring defects in checkpoint pathways respond to DNA damage improperly, which in turn may enhance the rate of cancer development. Ionizing radiation (IR) primarily leads to double-strand DNA breaks (DSBs), which activate DNA damage checkpoints to initiate signals ultimately leading to a binary decision between cell death and cell survival. TP53 has been recognized as an important checkpoint protein, functioning mainly through transcriptional control of target genes that influence multiple response pathways and leading to the diversity of responses to IR in mammalian cells. We review how the tumor suppressor P53 is involved in the complex response to IR to enforce the cell's fate to live by inducing the growth arrest coupled to DNA damage repair or to die by inducing irreversible growth arrest or apoptosis. Moreover, recent insights have emerged in our understanding of how P53 modulates radiosensitivity in tissues following IR as well as its role in sensitizing cells to chemo-and radiotherapy. The P53 pathway remains an attractive target for exploitation in the war on cancer.

show abstract

The role of DNA double strand breaks in lonizing radiation‐induced killing of eukaryotic cells

Cited by 293 publications

References 57 publications

Delayed chromosomal instability induced by DNA damage.

Delayed chromosomal instability induced by DNA damage.

DNA-Dependent Protein Kinase Is a Molecular Target for the Development of Noncytotoxic Radiation–Sensitizing Drugs

P53 and radiation responses

Contact Info

Product

Resources

About