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The checkpoint mediator protein Claspin is indispensable for the ATR-dependent phosphorylation of Chk1 in response to stalled DNA replication forks in Xenopus egg extracts. We show that Claspin also participates in the detection of chromosomal double-stranded DNA breaks (DSBs) in this system. Significantly, removal of Claspin from egg extracts only partially abrogates the activation of Chk1 in response to chromatin with DSBs, whereas depletion of both Claspin and BRCA1 completely abolishes this activation. The function of Claspin in this DSB-triggered pathway depends on phosphorylation of T817 and S819 by ATR. Conversely, neither phosphorylation of Claspin on these sites nor the presence of BRCA1 is necessary for activation of Chk1 in response to stalled replication forks. Thus, site-specific phosphorylation of a checkpoint mediator protein is a crucial determinant in the discrimination between various checkpoint-inducing structures. Furthermore, checkpoint mediator proteins exhibit functional overlap that varies depending on the nature of the checkpoint-triggering DNA signal.
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Abraham,
Cell cycle checkpoint signaling through the ATM and ATR kinases.
2001, Pubmed
Abraham,
Cell cycle checkpoint signaling through the ATM and ATR kinases.
2001,
Pubmed
Bakkenist,
Initiating cellular stress responses.
2004,
Pubmed
Canman,
Activation of the ATM kinase by ionizing radiation and phosphorylation of p53.
1998,
Pubmed
Chini,
Human claspin is required for replication checkpoint control.
2003,
Pubmed
,
Xenbase
Costanzo,
Reconstitution of an ATM-dependent checkpoint that inhibits chromosomal DNA replication following DNA damage.
2000,
Pubmed
,
Xenbase
Costanzo,
An ATR- and Cdc7-dependent DNA damage checkpoint that inhibits initiation of DNA replication.
2003,
Pubmed
,
Xenbase
Dasso,
Completion of DNA replication is monitored by a feedback system that controls the initiation of mitosis in vitro: studies in Xenopus.
1990,
Pubmed
,
Xenbase
Guo,
Response of Xenopus Cds1 in cell-free extracts to DNA templates with double-stranded ends.
2000,
Pubmed
,
Xenbase
Guo,
Requirement for Atr in phosphorylation of Chk1 and cell cycle regulation in response to DNA replication blocks and UV-damaged DNA in Xenopus egg extracts.
2000,
Pubmed
,
Xenbase
Hekmat-Nejad,
Xenopus ATR is a replication-dependent chromatin-binding protein required for the DNA replication checkpoint.
,
Pubmed
,
Xenbase
Jeong,
Phosphorylated claspin interacts with a phosphate-binding site in the kinase domain of Chk1 during ATR-mediated activation.
2003,
Pubmed
,
Xenbase
Joukov,
Functional communication between endogenous BRCA1 and its partner, BARD1, during Xenopus laevis development.
2001,
Pubmed
,
Xenbase
Katou,
S-phase checkpoint proteins Tof1 and Mrc1 form a stable replication-pausing complex.
2003,
Pubmed
Kobayashi,
Focus-formation of replication protein A, activation of checkpoint system and DNA repair synthesis induced by DNA double-strand breaks in Xenopus egg extract.
2002,
Pubmed
,
Xenbase
Kumagai,
14-3-3 proteins act as negative regulators of the mitotic inducer Cdc25 in Xenopus egg extracts.
1998,
Pubmed
,
Xenbase
Kumagai,
The Xenopus Chk1 protein kinase mediates a caffeine-sensitive pathway of checkpoint control in cell-free extracts.
1998,
Pubmed
,
Xenbase
Kumagai,
Claspin and the activated form of ATR-ATRIP collaborate in the activation of Chk1.
2004,
Pubmed
,
Xenbase
Kumagai,
Claspin, a novel protein required for the activation of Chk1 during a DNA replication checkpoint response in Xenopus egg extracts.
2000,
Pubmed
,
Xenbase
Kumagai,
Repeated phosphopeptide motifs in Claspin mediate the regulated binding of Chk1.
2003,
Pubmed
,
Xenbase
Lee,
Roles of replication fork-interacting and Chk1-activating domains from Claspin in a DNA replication checkpoint response.
2005,
Pubmed
,
Xenbase
Lee,
Claspin, a Chk1-regulatory protein, monitors DNA replication on chromatin independently of RPA, ATR, and Rad17.
2003,
Pubmed
,
Xenbase
Li,
Absence of BLM leads to accumulation of chromosomal DNA breaks during both unperturbed and disrupted S phases.
2004,
Pubmed
,
Xenbase
Lin,
Human Claspin works with BRCA1 to both positively and negatively regulate cell proliferation.
2004,
Pubmed
,
Xenbase
Liu,
Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint.
2000,
Pubmed
Lupardus,
A requirement for replication in activation of the ATR-dependent DNA damage checkpoint.
2002,
Pubmed
,
Xenbase
Mahbubani,
Cell cycle regulation of the replication licensing system: involvement of a Cdk-dependent inhibitor.
1997,
Pubmed
,
Xenbase
McGarry,
Geminin, an inhibitor of DNA replication, is degraded during mitosis.
1998,
Pubmed
,
Xenbase
Nyberg,
Toward maintaining the genome: DNA damage and replication checkpoints.
2002,
Pubmed
Osborn,
Checking on the fork: the DNA-replication stress-response pathway.
2002,
Pubmed
Osborn,
Mrc1 is a replication fork component whose phosphorylation in response to DNA replication stress activates Rad53.
2003,
Pubmed
Sancar,
Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints.
2004,
Pubmed
Stokes,
DNA replication is required for the checkpoint response to damaged DNA in Xenopus egg extracts.
2002,
Pubmed
,
Xenbase
Wang,
53BP1, a mediator of the DNA damage checkpoint.
2002,
Pubmed
Yarden,
BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage.
2002,
Pubmed
Yoo,
Mcm2 is a direct substrate of ATM and ATR during DNA damage and DNA replication checkpoint responses.
2004,
Pubmed
,
Xenbase
Yoo,
Adaptation of a DNA replication checkpoint response depends upon inactivation of Claspin by the Polo-like kinase.
2004,
Pubmed
,
Xenbase
Zhao,
ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1.
2001,
Pubmed
van Attikum,
The histone code at DNA breaks: a guide to repair?
2005,
Pubmed
