KU70/80, DNA-PKcs, and Artemis are essential for the rapid induction of apoptosis after massive DSB formation

被引：59

作者：

Abe, Takuya ^{[1
]}

Ishiai, Masamichi ^{[2
]}

Hosono, Yoshifumi ^{[1
]}

Yoshimura, Akari ^{[1
]}

Tada, Shusuke ^{[1
]}

Adachi, Noritaka ^{[3
]}

Koyama, Hideki ^{[3
]}

Takata, Minoru ^{[2
]}

Takeda, Shunichi ^{[4
]}

Enomoto, Takemi ^{[1
,5
]}

Seki, Masayuki ^{[1
]}

机构：

[1] Tohoku Univ, Grad Sch Pharmaceut Sci, Mol Cell Biol Lab, Aoba Ku, Sendai, Miyagi 9808578, Japan

[2] Kyoto Univ, Ctr Radiat Biol, Late Effect Studies, Sakyo Ku, Kyoto 6068501, Japan

[3] Yokohama City Univ, Grad Sch Integrated Sci, Kihara Inst Biol Res, Totsuka Ku, Yokohama, Kanagawa 2440813, Japan

[4] Kyoto Univ, Fac Med, Dept Radiat Genet, Crest Lab, Kyoto 6068501, Japan

[5] Tohoku Univ, 21st Century COE Program, Comprehens Res & Educ Ctr Planning Drug Dev & Cli, Sendai, Miyagi 9808578, Japan

来源：

CELLULAR SIGNALLING | 2008年 / 20卷 / 11期

关键词：

Apoptosis; DNA-PKcs; KU70; Artemis; NHEJ; DT40; Etoposide;

D O I：

10.1016/j.cellsig.2008.07.006

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 [细胞生物学]; 090102 [作物遗传育种];

摘要：

KU70(-/-) and DNA-PKcs(-/-/-)chicken DT40 cells are reportedly highly sensitive to the DNA topoisomerase II inhibitor etoposide. Here we report that KU70 and DNA-PKcs unexpectedly function together during the induction of apoptosis after exposure to high levels of etoposide. in the presence of 100 mu M etoposide, apoptosis was induced within 1 h in wild type DT40 cells but not in KU70(-/-) and DNA-PKcs(-/-/-) cells. In addition, the DNA-PK inhibitors NU7026 and wortmannin, as well as the caspase inhibitor Z-VAD-FMK, inhibited etoposide-induced apoptosis in wild type cells. Although Artemis(-/-) cells also showed defects in the etoposide-induced apoptosis, the other mutants defective in nonhomologous end-joining (NHEJ), LIG4(-/-), XRCC4(-), and XLF-/- cells were capable to induce apoptosis. When cells Were treated with high doses of etoposide, the chromatin binding of DNA-PKcs was impaired by deletion of KU70 but not of Artemis, suggesting that KU70 acts upstream of DNA-PKcs and Artemis acts downstream of DNA-PKcs in the apoptotic pathway like the NHEJ pathway. These results suggest that the proteins involved in the early stage of NHEJ pathway including Artemis but not the downstream factors decide the cell fate by selecting apoptosis or DNA repair according to the degree of DNA damage. (c) 2008 Elsevier Inc. All rights reserved.

引用

页码：1978 / 1985

页数：8

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