Inhibiting DNA-PKcs in a non-homologous end-joining pathway in response to DNA double-strand breaks Journal Article
| Authors: | Dong, J.; Zhang, T.; Ren, Y.; Wang, Z.; Ling, C. C.; He, F.; Li, G. C.; Wang, C.; Wen, B. |
| Article Title: | 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 wildtype cells and that DSB repair was delayed. γH2AX was associated with phospho-Ataxiatelangiectasia 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. |
| Keywords: | nasopharyngeal carcinoma; non-homologous end-joining; double-strand break; dna-pkcs; nu7441 |
| Journal Title: | Oncotarget |
| Volume: | 8 |
| Issue: | 14 |
| ISSN: | 1949-2553 |
| Publisher: | Impact Journals |
| Date Published: | 2017-04-04 |
| Start Page: | 22662 |
| End Page: | 22673 |
| Language: | English |
| DOI: | 10.18632/oncotarget.15153 |
| PROVIDER: | scopus |
| PUBMED: | 28186989 |
| PMCID: | PMC5410253 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 May 2017 -- Source: Scopus |
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