DNA-PK: the Major Target for Wortmannin-mediated Radiosensitization by the Inhibition of DSB Repair via NHEJ Pathway
| Autor: | Hiroshi Utsumi, Shunichi Takeda, Minoru Takata, Mitsumasa Hashimoto, Ken Ichi Yamamoto, Osamu Tokuno, Satish Rao |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
Radiation-Sensitizing Agents
DNA Repair Health Toxicology and Mutagenesis Lymphocyte Hamster DNA-Activated Protein Kinase Mice SCID Protein Serine-Threonine Kinases Chinese hamster Wortmannin Mice chemistry.chemical_compound Cricetulus Cricetinae medicine Animals Humans Radiology Nuclear Medicine and imaging Radiosensitivity Clonogenic assay Cells Cultured Radiation biology Chinese hamster ovary cell Nuclear Proteins DNA medicine.disease biology.organism_classification Molecular biology Androstadienes DNA-Binding Proteins medicine.anatomical_structure chemistry Ataxia-telangiectasia Chickens DNA Damage |
| Zdroj: | Journal of Radiation Research. 44:151-159 |
| ISSN: | 0449-3060 |
| DOI: | 10.1269/jrr.44.151 |
| Popis: | The effect of wortmannin posttreatment was studied in cells derived from different species (hamster, mouse, chicken, and human) with normal and defective DNA-dependent protein kinase (DNA-PK) activity, cells with and without the ataxia telangiectasia (ATM) gene, and cells lacking other regulatory proteins involved in the DNA double-strand break (DSB) repair pathways. Clonogenic assays were used to obtain all results. Wortmannin radiosensitization was observed in Chinese hamster cells (V79-B310H , CHO-K1), mouse mammary carcinoma cells (SR-1), transformed human fibroblast (N2KYSV), chicken B lymphocyte wild-type cells (DT40), and chicken Rad54 knockout cells (Rad54-/-). However, mouse mammary carcinoma cells (SX9) with defects in the DNA-PK and chicken DNA-PK catalytic subunit (DNA-PKcs) knockout cells (DNA-PKcs-/-/-) failed to exhibit wortmannin radiosensitization. On the other hand, SCID mouse cells (SC3VA2) exposed to wortmannin exhibited significant increases in radiosensitivity, possibly because of some residual function of DNA-PKcs. Moreover, the transformed human cells derived from AT patients (AT2KYSV) and chicken ATM knockout cells (ATM-/-) showed pronounced wortmannin radiosensitization. These studies demonstrate confirm that the mechanism underlying wortmannin radiosensitization is the inhibition of DNA-PK, but not of ATM, thereby resulting in the inhibition of DSB repair via nonhomologous endjoining (NHEJ). |
| Databáze: | OpenAIRE |
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