Mrc1 channels the DNA replication arrest signal to checkpoint kinase Cds1

Tanaka, Katsunori; Russell, Paul

doi:10.1038/ncb1101-966

Cited by 219 publications

(243 citation statements)

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“…ss, single-stranded. thought to function as a mediator or an adaptor in the ATRChk1 signaling pathway (4, 10, 12) in a manner similar to the two known mediators in yeast, scRad9 and Mrc1 proteins (6,7). However, recent work clearly demonstrated that Claspin is one of the first checkpoint proteins to associate with replicating chromatin (12) and hence has the potential to function as a replication fork sensor.…”

Section: Discussionmentioning

confidence: 99%

Human Claspin Is a Ring-shaped DNA-binding Protein with High Affinity to Branched DNA Structures

Sar

Lindsey-Boltz

Subramanian

et al. 2004

Journal of Biological Chemistry

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Claspin is an essential protein for the ATR-dependent activation of the DNA replication checkpoint response in Xenopus and human cells. Here we describe the purification and characterization of human Claspin. The protein has a ring-like structure and binds with high affinity to branched DNA molecules. These findings suggest that Claspin may be a component of the replication ensemble and plays a role in the replication checkpoint by directly associating with replication forks and with the various branched DNA structures likely to form at stalled replication forks because of DNA damage.

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Section: Discussionmentioning

confidence: 99%

Human Claspin Is a Ring-shaped DNA-binding Protein with High Affinity to Branched DNA Structures

Sar

Lindsey-Boltz

Subramanian

et al. 2004

Journal of Biological Chemistry

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“…The same 9-1-1 and Rad3-Rad26 checkpoint protein complexes may associate with the DNA replication complex [13]. However, the DNA replication checkpoint acts primarily through phosphorylation of Cds1 kinase, which is mediated by another protein Mrc1 [22,23], with minor participation of Chk1 kinase, and either kinase is sufficient by itself to give cell cycle arrest when DNA synthesis is inhibited [24]. Activated Cds1 kinase inactivates Cdc25 through a similar mechanism as Chk1 [1,24].…”

Section: Cell Cycle G2/m Controls and Check-pointsmentioning

confidence: 99%

Viral infections and cell cycle G2/M regulation

Zhao

Elder

2005

Cell Res

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Progression of cells from G2 phase of the cell cycle to mitosis is a tightly regulated cellular process that requires activation of the Cdc2 kinase, which determines onset of mitosis in all eukaryotic cells. In both human and fission yeast (Schizosaccharomyces pombe) cells, the activity of Cdc2 is regulated in part by the phosphorylation status of tyrosine 15 (Tyr15) on Cdc2, which is phosphorylated by Wee1 kinase during late G2 and is rapidly dephosphorylated by the Cdc25 tyrosine phosphatase to trigger entry into mitosis. These Cdc2 regulators are the downstream targets of two wellcharacterized G2/M checkpoint pathways which prevent cells from entering mitosis when cellular DNA is damaged or when DNA replication is inhibited. Increasing evidence suggests that Cdc2 is also commonly targeted by viral proteins, which modulate host cell cycle machinery to benefit viral survival or replication. In this review, we describe the effect of viral protein R (Vpr) encoded by human immunodeficiency virus type 1 (HIV-1) on cell cycle G2/M regulation. Based on our current knowledge about this viral effect, we hypothesize that Vpr induces cell cycle G2 arrest through a mechanism that is to some extent different from the classic G2/M checkpoints. One the unique features distinguishing Vpr-induced G2 arrest from the classic checkpoints is the role of phosphatase 2A (PP2A) in Vpr-induced G2 arrest. Interestingly, PP2A is targeted by a number of other viral proteins including SV40 small T antigen, polyomavirus T antigen, HTLV Tax and adenovirus E4orf4. Thus an in-depth understanding of the molecular mechanisms underlying Vpr-induced G2 arrest will provide additional insights into the basic biology of cell cycle G2/M regulation and into the biological significance of this effect during host-pathogen interactions.

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“…In fission yeast, two distinct checkpoints operate during different stages of the cell cycle to arrest cell cycle progression in response to DNA damage, or blocks to DNA replication. For example, in S phase, inhibition of replication fork progression by treatment with hydroxyurea (HU) leads to activation of the protein kinase Cds1, which delays G2 and stabilizes stalled replication forks (Lindsay et al, 1998;Alcasabas, 2001;Tanaka and Russell, 2001;Zhao et al, 2003;Tanaka and Russell, 2004;Zhao and Russell, 2004). Activation of Cds1 occurs downstream of the Rad-Hus signaling pathway that recognizes stalled forks and leads to activation of the ataxia-telangiectasia-mutated and ATM-and Rad3-related (ATM/ATR) homologue Rad3.…”

Section: Introductionmentioning

confidence: 99%

Activation of the DNA Damage Checkpoint in Mutants Defective in DNA Replication Initiation

Yin

Locovei

D’Urso

2008

MBoC

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In the fission yeast, Schizosaccharomyces pombe, blocks to DNA replication elongation trigger the intra-S phase checkpoint that leads to the activation of the Cds1 kinase. Cds1 is required to both prevent premature entry into mitosis and to stabilize paused replication forks. Interestingly, although Cds1 is essential to maintain the viability of mutants defective in DNA replication elongation, mutants defective in DNA replication initiation require the Chk1 kinase. This suggests that defects in DNA replication initiation can lead to activation of the DNA damage checkpoint independent of the intra-S phase checkpoint. This might result from reduced origin firing that leads to an increase in replication fork stalling or replication fork collapse that activates the G2 DNA damage checkpoint. We refer to the Chk1-dependent, Cds1-independent phenotype as the rid phenotype (for replication initiation defective). Chk1 is active in rid mutants, and rid mutant viability is dependent on the DNA damage checkpoint, and surprisingly Mrc1, a protein required for activation of Cds1. Mutations in Mrc1 that prevent activation of Cds1 have no effect on its ability to support rid mutant viability, suggesting that Mrc1 has a checkpoint-independent role in maintaining the viability of mutants defective in DNA replication initiation. INTRODUCTIONBefore cell division, all eukaryotic cells replicate their DNA through a highly regulated process that involves the binding of several proteins to origin DNA during the G1 phase of the cell cycle (Bell and Dutta, 2002;Diffley and Labib, 2002;Diffley, 2004). The first step in the initiation of DNA replication requires the binding of a six-member hetero-protein complex called Orc to replication origins, marking these sites for subsequent assembly of prereplicative complexes (pre-RCs). The assembly of pre-RCs is believed to occur in early G1, and it requires the loading of Mcm proteins to origin DNA. Two additional proteins Cdc18 and Cdt1 recruit Mcms to DNA and conversion of the pre-RC to an active initiation complex requires activation of both Cdk1 and Hsk1 kinases. Phosphorylation of key components of the pre-RC is believed to result in a reorganization of the origin-associated complex that allows the binding of additional replication proteins, including DNA polymerases and single-strand DNA binding protein. The Mcm complex, with its intrinsic ATPase activity, is believed to participate in the unwinding of DNA during DNA synthesis (Ishimi, 1997;Lee and Hurwitz, 2001).Analysis of cell cycle mutants in both Saccharomyces cerevisiae and Schizosaccharomyces pombe has led to the identification of a number of proteins that are involved in both the initiation and elongation of DNA replication. In addition to the previously mentioned Orc, Cdc18, Cdt1, and Mcm proteins, they include the Gins complex (Alberghina et al., 1983;Takayama et al., 2003;Gambus et al., 2006;Labib and Gambus, 2007), Sna41/Cdc45 (Miyake and Yamashita, 1998;Uchiyama et al., 2001a,b), Sld2, and Sld3 (Kamimura et al., 1998Nakajima an...

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Mrc1 channels the DNA replication arrest signal to checkpoint kinase Cds1

Cited by 219 publications

References 43 publications

Human Claspin Is a Ring-shaped DNA-binding Protein with High Affinity to Branched DNA Structures

Human Claspin Is a Ring-shaped DNA-binding Protein with High Affinity to Branched DNA Structures

Viral infections and cell cycle G2/M regulation

Activation of the DNA Damage Checkpoint in Mutants Defective in DNA Replication Initiation

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