DNA-PK

The major target for wortmannin-mediated radiosensitization by the inhibition of DSB repair via NHEJ pathway

Mitsumasa Hashimoto, Satish Rao, Osamu Tokuno, Ken Ichi Yamamoto, Minoru Takata, Shunichi Takeda, Hiroshi Utsumi

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

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).

Original languageEnglish
Pages (from-to)151-159
Number of pages9
JournalJournal of Radiation Research
Volume44
Issue number2
DOIs
Publication statusPublished - 06-2003

Fingerprint

DNA-Activated Protein Kinase
strands
deoxyribonucleic acid
chickens
proteins
asynchronous transfer mode
cells
mice
Chickens
hamsters
Catalytic Domain
cancer
ataxia
wortmannin
lymphocytes
fibroblasts
radiation tolerance
genes
Breast Neoplasms
Ataxia Telangiectasia

All Science Journal Classification (ASJC) codes

  • Radiation
  • Radiology Nuclear Medicine and imaging
  • Health, Toxicology and Mutagenesis

Cite this

Hashimoto, Mitsumasa ; Rao, Satish ; Tokuno, Osamu ; Yamamoto, Ken Ichi ; Takata, Minoru ; Takeda, Shunichi ; Utsumi, Hiroshi. / DNA-PK : The major target for wortmannin-mediated radiosensitization by the inhibition of DSB repair via NHEJ pathway. In: Journal of Radiation Research. 2003 ; Vol. 44, No. 2. pp. 151-159.
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abstract = "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).",
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DNA-PK : The major target for wortmannin-mediated radiosensitization by the inhibition of DSB repair via NHEJ pathway. / Hashimoto, Mitsumasa; Rao, Satish; Tokuno, Osamu; Yamamoto, Ken Ichi; Takata, Minoru; Takeda, Shunichi; Utsumi, Hiroshi.

In: Journal of Radiation Research, Vol. 44, No. 2, 06.2003, p. 151-159.

Research output: Contribution to journalArticle

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T2 - The major target for wortmannin-mediated radiosensitization by the inhibition of DSB repair via NHEJ pathway

AU - Hashimoto, Mitsumasa

AU - Rao, Satish

AU - Tokuno, Osamu

AU - Yamamoto, Ken Ichi

AU - Takata, Minoru

AU - Takeda, Shunichi

AU - Utsumi, Hiroshi

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N2 - 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).

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