Inhibiting DNA-PKcs in a non-homologous end-joining pathway in response to DNA double-strand breaks.

Abstract

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.

• Authors: Jun Dong, Tian Zhang, Yufeng Ren, Zhenyu Wang, Clifton C Ling, Fuqiu He, Gloria C Li, Chengtao Wang, Bixiu Wen
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 14 Pg. 22662-22673 (Apr 04 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28186989 (Publication Type: Journal Article)

Chemical References

• 8-dibenzothiophen-4-yl-2-morpholin-4-yl-chromen-4-one
• Chromones
• DNA-Binding Proteins
• Morpholines
• Nuclear Proteins
• Radiation-Sensitizing Agents
• Atr protein, mouse
• Ataxia Telangiectasia Mutated Proteins
• Checkpoint Kinase 1
• Chek1 protein, mouse
• DNA-Activated Protein Kinase
• Prkdc protein, mouse
• Xrcc6 protein, mouse
• Ku Autoantigen

Topics

• Animals
• Apoptosis
• Ataxia Telangiectasia Mutated Proteins (metabolism)
• Carcinoma (genetics, pathology)
• Cell Cycle Checkpoints (drug effects, radiation effects)
• Cell Proliferation
• Checkpoint Kinase 1 (metabolism)
• Chromones (pharmacology)
• DNA Breaks, Double-Stranded (drug effects)
• DNA End-Joining Repair (genetics)
• DNA-Activated Protein Kinase (antagonists & inhibitors, physiology)
• DNA-Binding Proteins (antagonists & inhibitors, physiology)
• Embryo, Mammalian (cytology, drug effects, radiation effects)
• Fibroblasts (cytology, drug effects, radiation effects)
• Ku Autoantigen (physiology)
• Mice
• Mice, Knockout
• Morpholines (pharmacology)
• Nasopharyngeal Carcinoma
• Nasopharyngeal Neoplasms (genetics, pathology)
• Nuclear Proteins (antagonists & inhibitors, physiology)
• Radiation Tolerance (genetics)
• Radiation, Ionizing
• Radiation-Sensitizing Agents (pharmacology)
• Tumor Cells, Cultured