Inactivation of DNA-PK by knockdown DNA-PKcs or NU7441 impairs non-homologous end-joining of radiation-induced double strand break repair Journal Article


Authors: Dong, J.; Ren, Y.; Zhang, T.; Wang, Z.; Ling, C. C.; Li, G. C.; He, F.; Wang, C.; Wen, B.
Article Title: Inactivation of DNA-PK by knockdown DNA-PKcs or NU7441 impairs non-homologous end-joining of radiation-induced double strand break repair
Abstract: The DNA-dependent protein kinase (DNA-PK) complex plays a pivotal role in non-homologous end-joining (NHEJ) repair. We investigated the mechanism of NU7441, a highly selective DNA-PK inhibitor, in NHEJ-competent mouse embryonic fibroblast (MEF) cells and NHEJ-deficient cells and explored the feasibility of its application in radiosen-sitizing nasopharyngeal carcinoma (NPC) cells. We generated wild-type and DNA-PKcs-/- MEF cells. Clonogenic survival assays, flow cytometry, and immunoblotting were performed to study the effect of NU7441 on survival, cell cycle, and DNA repair. NU7441 profoundly radiosensitized wild-type MEF cells and SUNE-1 cells, but not DNA-PKcs-/- MEF cells. NU7441 significantly suppressed radiation-induced DSB repair post-irradiation through unrepaired and lethal DNA damage, the cell cycle arrest. The effect was associated with the activation of cell cycle checkpoints. The present study revealed a mechanism by which inhibition of DNA-PK sensitizes cells to irradiation suggesting that radiotherapy in combination with DNA-PK inhibitor is a promising paradigm for the management of NPC which merits further investigation.
Keywords: controlled study; unclassified drug; human cell; nonhuman; cancer radiotherapy; flow cytometry; animal cell; mouse; dna damage; cell survival; cell cycle; dna repair; enzyme inhibition; protein kinase inhibitor; radiation injury; feasibility study; enzyme regulation; drug mechanism; enzyme inactivation; irradiation; immunoblotting; fibroblast; cell cycle arrest; cell cycle checkpoint; double stranded dna break; nasopharynx carcinoma; nasopharyngeal carcinoma; radiosensitizing agent; carcinoma cell; embryo cell; non-homologous end-joining; cell cloning; dna dependent protein kinase; dna-pk; dna dependent protein kinase catalytic subunit; double strand break; dna end joining repair; human; priority journal; article; mef cell line; nu7441; nu 7441; sune1 cell line
Journal Title: Oncology Reports
Volume: 39
Issue: 3
ISSN: 1021-335X
Publisher: Spandidos Publications  
Date Published: 2018-03-01
Start Page: 912
End Page: 920
Language: English
DOI: 10.3892/or.2018.6217
PROVIDER: scopus
PMCID: PMC5802037
PUBMED: 29344644
DOI/URL:
Notes: Article -- Export Date: 1 March 2018 -- Source: Scopus
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MSK Authors
  1. Gloria C Li
    121 Li
  2. Bixiu Wen
    21 Wen
  3. Fuqiu He
    21 He
  4. C Clifton Ling
    311 Ling