Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Proc Natl Acad Sci U S A
2004 Apr 27;10117:6484-9. doi: 10.1073/pnas.0401847101.
Show Gene links
Show Anatomy links
Human Claspin works with BRCA1 to both positively and negatively regulate cell proliferation.
Lin SY
,
Li K
,
Stewart GS
,
Elledge SJ
.
???displayArticle.abstract??? Claspin is a homolog of Mrc1, a checkpoint protein required for the DNA replication checkpoint in yeast. In Xenopus, phosphorylated Claspin binds to xChk1 and regulates xChk1 activation in response to replication stress. In this study, we have shown that the human homolog of Claspin is required for resistance to multiple forms of genotoxic stress including UV, IR, and hydroxyurea. Phosphorylation of Claspin was found to depend on the ataxia telangiectasia mutated-Rad3 related (ATR) pathway. DNA damage induces the formation of a complex between Claspin and BRCA1, a second regulator of Chk1 activation. Claspin was found to control BRCA1 phosphorylation on serine 1524, a site whose phosphorylation is controlled by the ATR pathway. These results are consistent with a model in which ATR regulates Claspin phosphorylation in response to DNA damage and replication stress resulting in recruitment and phosphorylation of BRCA1. BRCA1 and Claspin then function to activate the tumor suppressor Chk1. Unexpectedly, we found that Claspin has a second, positive role in control of the cell cycle as Claspin overexpression increased cell proliferation. These results suggest that Claspin has properties of both a tumor suppressor and an oncogene.
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
Alcasabas,
Mrc1 transduces signals of DNA replication stress to activate Rad53.
2001,
Pubmed
Chini,
Human claspin is required for replication checkpoint control.
2003,
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
Jin,
SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase.
2003,
Pubmed
Katou,
S-phase checkpoint proteins Tof1 and Mrc1 form a stable replication-pausing complex.
2003,
Pubmed
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,
Claspin, a Chk1-regulatory protein, monitors DNA replication on chromatin independently of RPA, ATR, and Rad17.
2003,
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
Matsuoka,
Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro.
2000,
Pubmed
Matsuoka,
Linkage of ATM to cell cycle regulation by the Chk2 protein kinase.
1998,
Pubmed
Melo,
A unified view of the DNA-damage checkpoint.
2002,
Pubmed
,
Xenbase
O'Driscoll,
A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome.
2003,
Pubmed
Osborn,
Mrc1 is a replication fork component whose phosphorylation in response to DNA replication stress activates Rad53.
2003,
Pubmed
Osborn,
Checking on the fork: the DNA-replication stress-response pathway.
2002,
Pubmed
Painter,
Radiosensitivity in ataxia-telangiectasia: a new explanation.
1980,
Pubmed
Sanchez,
Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25.
1997,
Pubmed
Shiloh,
ATM and ATR: networking cellular responses to DNA damage.
2001,
Pubmed
Tanaka,
Mrc1 channels the DNA replication arrest signal to checkpoint kinase Cds1.
2001,
Pubmed
Walworth,
DNA damage: Chk1 and Cdc25, more than meets the eye.
2001,
Pubmed
Wang,
53BP1, a mediator of the DNA damage checkpoint.
2002,
Pubmed
Xu,
Two molecularly distinct G(2)/M checkpoints are induced by ionizing irradiation.
2002,
Pubmed
Xu,
Involvement of Brca1 in S-phase and G(2)-phase checkpoints after ionizing irradiation.
2001,
Pubmed
Yarden,
BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage.
2002,
Pubmed
Zhao,
Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints.
2002,
Pubmed
Zou,
Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes.
2003,
Pubmed
