Involvement of DNA-dependent Protein Kinase in Normal Cell Cycle Progression through Mitosis

被引：70

作者：

Lee, Kyung-Jong ^{[1
]}

Lin, Yu-Fen ^{[1
]}

Chou, Han-Yi ^{[2
]}

Yajima, Hirohiko ^{[1
]}

Fattah, Kazi R. ^{[1
]}

Lee, Sheng-Chung ^{[2
]}

Chen, Benjamin P. C. ^{[1
]}

机构：

[1] Univ Texas SW Med Ctr Dallas, Div Mol Radiat Biol, Dept Radiat Oncol, Dallas, TX 75390 USA

[2] Natl Taiwan Univ, Inst Mol Med, Coll Med, Taipei 10051, Taiwan

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2011年 / 286卷 / 14期

基金：

美国国家卫生研究院; 美国国家航空航天局;

关键词：

DOUBLE-STRAND BREAK; INDUCED REPLICATION STRESS; CATALYTIC SUBUNIT; PHOSPHORYLATION SITES; KINETOCHORE CAPTURE; MITOTIC SPINDLE; IN-VIVO; CHECKPOINT; DAMAGE; LOCALIZATION;

D O I：

10.1074/jbc.M110.212969

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) plays an important role in DNA double-strand break (DSB) repair as the underlying mechanism of the non-homologous end joining pathway. When DSBs occur, DNA-PKcs is rapidly phosphorylated at both the Thr-2609 and Ser-2056 residues, and such phosphorylations are critical for DSB repair. In this study we report that, in addition to responding to DSBs, DNA-PKcs is activated and phosphorylated in normal cell cycle progression through mitosis. Mitotic induction of DNA-PKcs phosphorylation is closely associated with the spindle apparatus at centrosomes and kinetochores. Furthermore, depletion of DNA-PKcs protein levels or inhibition of DNA-PKcs kinase activity results in the delay of mitotic transition because of chromosome misalignment. These results demonstrate for the first time that DNA-PKcs, in addition to its role in DSB repair, is a critical regulator of mitosis and could modulate microtubule dynamics in chromosome segregation.

引用

页码：12796 / 12802

页数：7

共 31 条

[21] Inactivation of DNA-Dependent Protein Kinase Leads to Spindle Disruption and Mitotic Catastrophe with Attenuated Checkpoint Protein 2 Phosphorylation in Response to DNA Damage [J].

Shang, Zeng-Fu ;

Huang, Bo ;

Xu, Qin-Zhi ;

Zhang, Shi-Meng ;

Fan, Rong ;

Liu, Xiao-Dan ;

Wang, Yu ;

Zhou, Ping-Kun .

CANCER RESEARCH, 2010, 70 (09) :3657-3666

[22] The DNA-dependent protein kinase [J].

Smith, GCM ;

Jackson, SP .

GENES & DEVELOPMENT, 1999, 13 (08) :916-934

[23] Kinetochore capture and bi-orientation on the mitotic spindle [J].

Tanaka, TU ;

Stark, MJR ;

Tanaka, K .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2005, 6 (12) :929-942

[24] Phosphorylation of Cdc20 by Bub1 provides a catalytic mechanism for APC/C inhibition by the spindle checkpoint [J].

Tang, ZY ;

Shu, HJ ;

Oncel, D ;

Chen, S ;

Yu, HT .

MOLECULAR CELL, 2004, 16 (03) :387-397

[25] Kinetochore localization of murine Bub1 is required for normal mitotic timing and checkpoint response to spindle damage [J].

Taylor, SS ;

McKeon, F .

CELL, 1997, 89 (05) :727-735

[26] HURP controls spindle dynamics to promote proper interkinetochore tension and efficient kinetochore capture [J].

Wong, Jim ;

Fang, Guowei .

JOURNAL OF CELL BIOLOGY, 2006, 173 (06) :879-891

[27] A Role of DNA-PK for the Metabolic Gene Regulation in Response to Insulin [J].

Wong, Roger H. F. ;

Chang, Inhwan ;

Hudak, Carolyn S. S. ;

Hyun, Suzanne ;

Kwan, Hiu-Yee ;

Sul, Hei Sook .

CELL, 2009, 136 (06) :1056-1072

[28] ATR-dependent phosphorylation of DNA-dependent protein kinase catalytic subunit in response to UV-induced replication stress [J].

Yajima, Hirohiko ;

Lee, Kyung-Jong ;

Chen, Benjamin P. C. .

MOLECULAR AND CELLULAR BIOLOGY, 2006, 26 (20) :7520-7528

[29] DNA Double-Strand Break Formation upon UV-Induced Replication Stress Activates ATM and DNA-PKcs Kinases [J].

Yajima, Hrohiko ;

Lee, Kyung-Jong ;

Zhang, Shichuan ;

Kobayashi, Junya ;

Chen, Benjamin P. C. .

JOURNAL OF MOLECULAR BIOLOGY, 2009, 385 (03) :800-810

[30] Identification of a novel ubiquitin-conjugating enzyme involved in mitotic cyclin degradation [J].

Yu, HT ;

King, RW ;

Peters, JM ;

Kirschner, MW .

CURRENT BIOLOGY, 1996, 6 (04) :455-466

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