Regulatory interactions between the checkpoint kinase Chk1 and the proteins of the DNA-dependent protein kinase complex

被引:39
作者
Goudelock, DM [1 ]
Jiang, KC [1 ]
Pereira, E [1 ]
Russell, B [1 ]
Sanchez, Y [1 ]
机构
[1] Univ Cincinnati, Coll Med, Dept Mol Genet Biochem & Microbiol, Cincinnati, OH 45267 USA
关键词
D O I
10.1074/jbc.M301765200
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
Checkpoints are biochemical pathways that provide cells a mechanism to detect DNA damage and respond by arresting the cell cycle to allow DNA repair. The conserved checkpoint kinase, Chk1, regulates mitotic progression in response to DNA damage by blocking the activation of Cdk1/cyclin B. In this study, we investigate the regulatory interaction between Chk1 and members of the Atm family of kinases and the functional role of the C-terminal non-catalytic domains of Chk1. Chk1 stimulates the kinase activity of DNA-PK ( protein kinase) complexes, which leads to increased phosphorylation of p53 on Ser-15 and Ser-37. In addition, Chk1 stimulates DNA-PK-dependent end-joining reactions in vitro. We also show that Chk1 protein complexes bind to single-stranded DNA and DNA ends. These results indicate a connection between components that regulate the checkpoint pathways and DNA-PK complex proteins, which have a role in the repair of double strand breaks.
引用
收藏
页码:29940 / 29947
页数:8
相关论文
共 57 条
[11]  
Chehab NH, 2000, GENE DEV, V14, P278
[12]   Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage [J].
Chehab, NH ;
Malikzay, A ;
Stavridi, ES ;
Halazonetis, TD .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (24) :13777-13782
[13]   The 1.7 Å crystal structure of human cell cycle checkpoint kinase Chk1:: Implications for Chk1 regulation [J].
Chen, P ;
Luo, C ;
Deng, YL ;
Ryan, K ;
Register, J ;
Margosiak, S ;
Tempczyk-Russell, A ;
Nguyen, B ;
Myers, P ;
Lundgren, K ;
Kan, CC ;
O'Connor, PM .
CELL, 2000, 100 (06) :681-692
[14]   Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints [J].
Cliby, WA ;
Roberts, CJ ;
Cimprich, KA ;
Stringer, CM ;
Lamb, JR ;
Schreiber, SL ;
Friend, SH .
EMBO JOURNAL, 1998, 17 (01) :159-169
[15]   Cell cycle checkpoints: Preventing an identity crisis [J].
Elledge, SJ .
SCIENCE, 1996, 274 (5293) :1664-1672
[16]   Cdc25 mitotic inducer targeted by Chk1 DNA damage checkpoint kinase [J].
Furnari, B ;
Rhind, N ;
Russell, P .
SCIENCE, 1997, 277 (5331) :1495-1497
[17]   The Chk1 protein kinase and the Cdc25C regulatory pathways are targets of the anticancer agent UCN-01 [J].
Graves, PR ;
Yu, LJ ;
Schwarz, JK ;
Gales, J ;
Sausville, EA ;
O'Connor, PM ;
Piwnica-Worms, H .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (08) :5600-5605
[18]   DNA repair - Gatekeepers of recombination [J].
Haber, JE .
NATURE, 1999, 398 (6729) :665-+
[19]   ATR is a caffeine-sensitive, DNA-activated protein kinase with a substrate specificity distinct from DNA-PK [J].
Hall-Jackson, CA ;
Cross, DAE ;
Morrice, N ;
Smythe, C .
ONCOGENE, 1999, 18 (48) :6707-6713
[20]   DNA damage-induced activation of p53 by the checkpoint kinase Chk2 [J].
Hirao, A ;
Kong, YY ;
Matsuoka, S ;
Wakeham, A ;
Ruland, J ;
Yoshida, H ;
Liu, D ;
Elledge, SJ ;
Mak, TW .
SCIENCE, 2000, 287 (5459) :1824-1827