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 - Jun 2003
Externally publishedYes

Fingerprint

DNA-Activated Protein Kinase
protein kinases
strands
deoxyribonucleic acid
chickens
proteins
asynchronous transfer mode
DNA
cells
mice
Chickens
hamsters
protein subunits
Catalytic Domain
cancer
ataxia
breast neoplasms
wortmannin
lymphocytes
fibroblasts

Keywords

  • Chicken knockout cells
  • DNA-PK
  • Radiosensitization ATM
  • SCID cells
  • Wortmannin

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Radiology Nuclear Medicine and imaging
  • Radiological and Ultrasound Technology
  • Radiation

Cite this

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

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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