|
|
|
|
|
|
|
|
|||||
| Home Help Feedback Subscriptions Archive Search Table of Contents | |||||
First published online December 22, 2004
doi: 10.1242/10.1242/jcs.01626
Commentary |
1 Department of Oncological Sciences, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1130, New York, NY 10029, USA
2 Stanford University, Department of Molecular Pharmacology, 318 Campus Drive, Stanford, CA 94305, USA
* Author for correspondence (e-mail: matthew.oconnell{at}mssm.edu)
Cells mount a coordinated response to DNA damage, activating DNA repair pathways and cell-cycle checkpoint pathways to allow time for DNA repair to occur. In human cells, checkpoint responses can be divided into p53-dependent and p53-independent pathways, the latter being predominant in G2 phase of the cell cycle. The p53-independent pathway involves a phosphorylation cascade that activates the Chk1 effector kinase and induces G2 arrest through inhibitory tyrosine phosphorylation of Cdc2. At the top of this cascade are the ATR and ATM kinases. How ATM and ATR recognize DNA damage and activate this checkpoint pathway is only beginning to emerge. Single-stranded DNA, a result of stalled DNA replication or processing of chromosomal lesions, appears to be central to the activation of ATR. The recruitment of replication protein A to single-stranded DNA facilitates the recruitment of several complexes of checkpoint proteins. In this context, ATR is activated and then phosphorylates the C-terminus of Chk1, activating it to enforce a block to mitotic entry.
Key words: DNA damage, Cell-cycle checkpoint control, ATR, ATM, Chk1
This article has been cited by other articles:
|
|
 |
|
  Y. Yan, C. P. Black, P. T. Cao, J. L. Haferbier, R. H. Kolb, R. S. Spieker, A. M. Ristow, and K. H. Cowan {gamma}-Irradiation-Induced DNA Damage Checkpoint Activation Involves Feedback Regulation between Extracellular Signal-Regulated Kinase 1/2 and BRCA1 Cancer Res., July 1, 2008; 68(13): 5113 - 5121. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Satyanarayana, M. B. Hilton, and P. Kaldis p21 Inhibits Cdk1 in the Absence of Cdk2 to Maintain the G1/S Phase DNA Damage Checkpoint Mol. Biol. Cell, January 1, 2008; 19(1): 65 - 77. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Errico, V. Costanzo, and T. Hunt Tipin is required for stalled replication forks to resume DNA replication after removal of aphidicolin in Xenopus egg extracts PNAS, September 18, 2007; 104(38): 14929 - 14934. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kosoy, T. M. Calonge, E. A. Outwin, and M. J. O'Connell Fission Yeast Rnf4 Homologs Are Required for DNA Repair J. Biol. Chem., July 13, 2007; 282(28): 20388 - 20394. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. H. Luo, K. Rosenke, K. Czornak, and E. A. Fortunato Human Cytomegalovirus Disrupts both Ataxia Telangiectasia Mutated Protein (ATM)- and ATM-Rad3-Related Kinase-Mediated DNA Damage Responses during Lytic Infection J. Virol., February 15, 2007; 81(4): 1934 - 1950. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. K. Mirzoeva, T. Kawaguchi, and R. O. Pieper The Mre11/Rad50/Nbs1 complex interacts with the mismatch repair system and contributes to temozolomide-induced G2 arrest and cytotoxicity. Mol. Cancer Ther., November 1, 2006; 5(11): 2757 - 2766. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Hashimoto, T. Tsujimura, A. Sugino, and H. Takisawa The phosphorylated C-terminal domain of Xenopus Cut5 directly mediates ATR-dependent activation of Chk1. Genes Cells, September 1, 2006; 11(9): 993 - 1007. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Taricani and T. S.F. Wang Rad4TopBP1, a Scaffold Protein, Plays Separate Roles in DNA Damage and Replication Checkpoints and DNA Replication Mol. Biol. Cell, August 1, 2006; 17(8): 3456 - 3468. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Karnitz, K. S. Flatten, J. M. Wagner, D. Loegering, J. S. Hackbarth, S. J. H. Arlander, B. T. Vroman, M. B. Thomas, Y.-U. Baek, K. M. Hopkins, et al. Gemcitabine-Induced Activation of Checkpoint Signaling Pathways That Affect Tumor Cell Survival Mol. Pharmacol., December 1, 2005; 68(6): 1636 - 1644. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Lee, D. A. Gold, A. Shevchenko, A. Shevchenko, and W. G. Dunphy Roles of Replication Fork-interacting and Chk1-activating Domains from Claspin in a DNA Replication Checkpoint Response Mol. Biol. Cell, November 1, 2005; 16(11): 5269 - 5282. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. A. Mesa, D. Loegering, H. L. Powell, K. Flatten, S. J. H. Arlander, N. T. Dai, M. P. Heldebrant, B. T. Vroman, B. D. Smith, J. E. Karp, et al. Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine Blood, July 1, 2005; 106(1): 318 - 327. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Karnitz and S. J. H. Arlander Chk1, a Novel Target to Sensitize Tumor Cells to Replication Inhibitors Am. Assoc. Cancer Res. Educ. Book, April 1, 2005; 2005(1): 254 - 257. [Full Text] [PDF]
|
|
