Inhibiting DNA-PKcs in a non-homologous end-joining pathway in response to DNA double-strand breaks
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Jun Dong1,*, Tian Zhang1,*, Yufeng Ren1,*, Zhenyu Wang1,*, Clifton C. Ling2, Fuqiu He2, Gloria C. Li2, Chengtao Wang1, Bixiu Wen1,2
1Department of Radiation Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China
2Department of Medical Physics and Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA
Bixiu Wen, email: firstname.lastname@example.org
Chengtao Wang, email: email@example.com
Keywords: DNA-PKcs, non-homologous end-joining, double-strand break, NU7441, nasopharyngeal carcinoma
Received: September 08, 2016 Accepted: January 25, 2017 Published: February 07, 2017
DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a distinct factor in the non-homologous end-joining (NHEJ) pathway involved in DNA double-strand break (DSB) repair. We examined the crosstalk between key proteins in the DSB NHEJ repair pathway and cell cycle regulation and found that mouse embryonic fibroblast (MEF) cells deficient in DNA-PKcs or Ku70 were more vulnerable to ionizing radiation (IR) compared with wild-type cells and that DSB repair was delayed. γH2AX was associated with phospho-Ataxia-telangiectasia mutated kinase (Ser1987) and phospho-checkpoint effector kinase 1 (Ser345) foci for the arrest of cell cycle through the G2/M phase. Inhibition of DNA-PKcs prolonged IR-induced G2/M phase arrest because of sequential activation of cell cycle checkpoints. DSBs were introduced, and cell cycle checkpoints were recruited after exposure to IR in nasopharyngeal carcinoma SUNE-1 cells. NU7441 radiosensitized MEF cells and SUNE-1 cells by interfering with DSB repair. Together, these results reveal a mechanism in which coupling of DSB repair with the cell cycle radiosensitizes NHEJ repair-deficient cells, justifying further development of DNA-PK inhibitors in cancer therapy.
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