Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase

被引:140
作者
Beck, Halfdan [1 ]
Nahse, Viola [2 ]
Larsen, Marie Sofie Yoo [1 ]
Groth, Petra [4 ]
Clancy, Trevor [3 ]
Lees, Michael [1 ]
Jorgensen, Mette [1 ]
Helleday, Thomas [4 ,5 ]
Syljuasen, Randi G. [2 ]
Sorensen, Claus Storgaard [1 ]
机构
[1] Univ Copenhagen, Biotech Res & Innovat Ctr, DK-2200 Copenhagen N, Denmark
[2] Oslo Univ Hosp, Dept Radiat Biol, N-0310 Oslo, Norway
[3] Oslo Univ Hosp, Norwegian Radium Hosp, Inst Canc Res, Dept Tumor Biol, N-0310 Oslo, Norway
[4] Stockholm Univ, Dept Genet Microbiol & Toxicol, S-10691 Stockholm, Sweden
[5] Univ Oxford, Gray Inst Radiat Oncol & Biol, Oxford OX3 7DQ, England
基金
英国医学研究理事会;
关键词
DNA-DAMAGE; CHK1; PHOSPHORYLATION; CHECKPOINTS; INITIATION; NETWORK; MITOSIS; ENTRY; CDC2;
D O I
10.1083/jcb.200905059
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Maintenance of genome integrity is of critical importance to cells. To identify key regulators of genomic integrity, we screened a human cell line with a kinome small interfering RNA library. WEE1, a major regulator of mitotic entry, and CHK1 were among the genes identified. Both kinases are important negative regulators of CDK1 and -2. Strikingly, WEE1 depletion rapidly induced DNA damage in S phase in newly replicated DNA, which was accompanied by a marked increase in single-stranded DNA. This DNA damage is dependent on CDK1 and -2 as well as the replication proteins MCM2 and CDT1 but not CDC25A. Conversely, DNA damage after CHK1 inhibition is highly dependent on CDC25A. Furthermore, the inferior proliferation of CHK1-depleted cells is improved substantially by codepletion of CDC25A. We conclude that the mitotic kinase WEE1 and CHK1 jointly maintain balanced cellular control of Cdk activity during normal DNA replication, which is crucial to prevent the generation of harmful DNA lesions during replication.
引用
收藏
页码:629 / 638
页数:10
相关论文
共 25 条
[1]  
Bader GD, 2003, NUCLEIC ACIDS RES, V31, P248, DOI 10.1093/nar/gkg056
[2]   DNA damage checkpoints: from initiation to recovery or adaptation [J].
Bartek, Jiri ;
Lukas, Jiri .
CURRENT OPINION IN CELL BIOLOGY, 2007, 19 (02) :238-245
[3]   Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints [J].
Bartkova, Jirina ;
Rezaei, Nousin ;
Liontos, Michalis ;
Karakaidos, Panagiotis ;
Kletsas, Dimitris ;
Issaeva, Natalia ;
Vassiliou, Leandros-Vassilios F. ;
Kolettas, Evangelos ;
Niforou, Katerina ;
Zoumpourlis, Vassilis C. ;
Takaoka, Munenori ;
Nakagawa, Hiroshi ;
Tort, Frederic ;
Fugger, Kasper ;
Johansson, Fredrik ;
Sehested, Maxwell ;
Andersen, Claus L. ;
Dyrskjot, Lars ;
Orntoft, Torben ;
Lukas, Jiri ;
Kittas, Christos ;
Helleday, Thomas ;
Halazonetis, Thanos D. ;
Bartek, Jiri ;
Gorgoulis, Vassilis G. .
NATURE, 2006, 444 (7119) :633-637
[4]   The DNA damage response during an unperturbed S-phase [J].
Ben-Yehoyada, Merav ;
Gautier, Jean ;
Dupre, Aude .
DNA REPAIR, 2007, 6 (07) :914-922
[5]  
Chen Y, 2008, FRONT BIOSCI-LANDMRK, V13, P5016
[6]   Differential contribution of inhibitory phosphorylation of CDC2 and CDK2 for unperturbed cell cycle control and DNA integrity checkpoints [J].
Chow, JPH ;
Siu, WY ;
Ho, HTB ;
Ma, KHT ;
Ho, CC ;
Poon, RYC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (42) :40815-40828
[7]   CDC2 REGULATORY FACTORS [J].
COLEMAN, TR ;
DUNPHY, WG .
CURRENT OPINION IN CELL BIOLOGY, 1994, 6 (06) :877-882
[8]   Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication [J].
Di Micco, Raffaella ;
Fumagalli, Marzia ;
Cicalese, Angelo ;
Piccinin, Sara ;
Gasparini, Patrizia ;
Luise, Chiara ;
Schurra, Catherine ;
Garre, Massimiliano ;
Nuciforo, Paolo Giovanni ;
Bensimon, Aaron ;
Maestro, Roberta ;
Pelicci, Pier Giuseppe ;
di Fagagna, Fabrizio d'Adda .
NATURE, 2006, 444 (7119) :638-642
[9]   An oncogene-induced DNA damage model for cancer development [J].
Halazonetis, Thanos D. ;
Gorgoulis, Vassilis G. ;
Bartek, Jiri .
SCIENCE, 2008, 319 (5868) :1352-1355
[10]   Conservation of mechanisms controlling entry into mitosis: Budding yeast Wee1 delays entry into mitosis and is required for cell size control [J].
Harvey, SL ;
Kellogg, DR .
CURRENT BIOLOGY, 2003, 13 (04) :264-275