Claspin and the Activated Form of ATR-ATRIP Collaborate in the Activation of Chk1

Kumagai, Akiko; Kim, Soomi; Dunphy, William G.

doi:10.1074/jbc.m408353200

Cited by 127 publications

(155 citation statements)

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“…Claspin had originally being identified as a protein that interacts with Chk1 after DNA damage and regulates Chk1 activation. The original hypothesis is that Claspin may work as an adaptor molecule mediating ATR-dependent Chk1 activation (Kumagai et al, 2004). However, it is still not clear how Claspin contributes to Chk1 activation.…”

Section: Discussionmentioning

confidence: 99%

“…Downregulation of human Claspin Lin et al, 2004) decreases Chk1 activation in response to hydroxyurea (HU), ionizing radiation (IR) and UV, while immunodepletion of Xenopus Claspin (Kumagai and Dunphy, 2000) inhibits Chk1 activation induced by DNA templates in egg extracts. In addition, it has been shown in vitro for both Xenopus (Kumagai et al, 2004) and human systems (Clarke and Clarke, 2005) that the presence of Claspin is required for the ATR/ATM-dependent phosphorylation of Chk1. Furthermore, Claspin has been shown to be involved in regulation of the S-phase checkpoint, cell survival, and prevention of premature mitosis Lin et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Chk1 is required to maintain Claspin stability

2006

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Chk1 is required to maintain Claspin stability

2006

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“…8,9 A key player in mediating the ATRdependent activation of Chk1 is Claspin. 10,11 In Xenopus and human cells, Claspin is phosphorylated in response to DNA damage in an ATR-dependent manner, 12 promoting the association of Claspin with Chk1 and facilitating Chk1 activation and subsequent checkpoint arrest. 10 Both Claspin and its homologue in yeast, Mrc1, are involved in the checkpoint that is triggered in the presence of stalled replication forks during S phase of the cell cycle.…”

mentioning

confidence: 99%

Cleavage and degradation of Claspin during apoptosis by caspases and the proteasome

et al. 2007

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Apoptosis plays a crucial role in development and tissue homeostasis. Some key survival pathways, such as DNA damage checkpoints and DNA repair, have been described to be inactivated during apoptosis. Here, we describe the processing of the human checkpoint protein Claspin during apoptosis. We observed cleavage of Claspin into multiple fragments in vivo. In vitro cleavage with caspases 3 and 7 of various fragments of the protein, revealed cut sites near the N-and C-termini of the protein.Using mass spectrometry, we identified a novel caspase cleavage site in Claspin at Asp25. Importantly, in addition to cleavage by caspases, we observed a proteasome-dependent degradation of Claspin under apoptotic conditions, resulting in a reduction of the levels of both full-length Claspin and its cleavage products. This degradation was not dependent upon the DSGxxS phosphodegron motif required for SCF b-TrCP -mediated ubiquitination of Claspin. Finally, downregulation of Claspin protein levels by short interfering RNA resulted in an increase in apoptotic induction both in the presence and absence of DNA damage. We conclude that Claspin has antiapoptotic activity and is degraded by two different pathways during apoptosis. The resulting disappearance of Claspin from the cells further promotes apoptosis.

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“…1 Timeless, Tipin and Claspin are mediators of ATR phosphorylation of Chk1 in response to DNA damage and replication stress. [3][4][5][6][7][8] Timeless and Tipin form a heterodimer and are components of the "replication fork protection complex" (RFPC), named for the timeless-tipin complex and Claspin are mediators of the AtR-dependent activation of Chk1 in the intra-S checkpoint response to stalled DNA replication forks. tim-tipin and Claspin also contribute to sister chromatid cohesion (SCC) in various organisms, likely through a replication-coupled process.…”

Section: Introductionmentioning

confidence: 99%