Replication checkpoint requires phosphorylation of the phosphatase Cdc25 by Cds1 or Chk1

Zeng, Yan; Forbes, Kristi Chrispell; Wu, Zijuan; Moreno, Sergio; Piwnica‐Worms, Helen; Enoch, Tamar

doi:10.1038/26766

Cited by 319 publications

(355 citation statements)

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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%

“…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]. Cds1 also activates the Mik1 kinase, which phosphorylate Tyr15 of Cdc2 [25].…”

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

confidence: 99%

“…None of the early checkpoint-specific mutants (rad1, rad3, rad9 and rad17) showed a significant effect on the induction of G2 arrest by Vpr [38,39,46]. Furthermore, mutations in both chk1 and cds1, which are thought to be the last steps specific for the checkpoint [1,18,24], also do not block Vprinduced G2 arrest [39,46]. Therefore, Vpr does not appear to use the DNA-damage or DNA-replication checkpoint pathways to induce G2 arrest in fission yeast.…”

Section: Cell Cycle G2/m Arrest Induced By Hiv-1 Vprmentioning

confidence: 99%

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

confidence: 99%

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

confidence: 99%

Section: Cell Cycle G2/m Arrest Induced By Hiv-1 Vprmentioning

confidence: 99%

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Viral infections and cell cycle G2/M regulation

Zhao

Elder

2005

Cell Res

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“…Recent work has identi®ed the mitotic inducer cdc25 as the target for this checkpoint pathway. Chk1 and cds1 are protein kinases which, when active, phosphorylate cdc25 (Zeng et al, 1998). This, in turn, promotes the binding of a 14-3-3 protein (Furnari et al, 1997;Peng et al, 1997;Sanchez et al, 1997), which escorts cdc25 out of the nucleus and thus prevents activation of the mitotic cyclin B/cdc2 kinase (Lopez-Girona et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

ATR is a caffeine-sensitive, DNA-activated protein kinase with a substrate specificity distinct from DNA-PK

et al. 1999

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ATR is a large, 4300 kDa protein containing a carboxy-terminus kinase domain related to PI-3 kinase, and is homologous to the ATM gene product in human cells and the rad3/MEC1 proteins in yeast. These proteins, together with the DNA-PK, are part of a new family of PI-3 kinase related proteins. All members of this family play important roles in checkpoints which operate to permit cell survival following many forms of DNA damage. We have expressed ATR protein in HEK293 cells and puri®ed the protein to near-homogeneity. We show that pure ATR is a protein kinase which is activated by circular single-stranded, doublestranded or linear DNA. Thus ATR is a new member of a sub-family of PIK related kinases, founded by the DNA-PK, which are activated in the presence of DNA. Unlike DNA-PK, ATR does not appear to require Ku proteins for its activation by DNA. We show directly that, like ATM and DNA-PK, ATR phosphorylates the genome surveillance protein p53 on serine 15, a site which is up-regulated in response to DNA damage. In addition, we ®nd that ATR has a substrate speci®city similar to, but unique from, the DNA-PK in vitro, suggesting that these proteins have overlapping but distinct functions in vivo. Finally, we ®nd that the kinase activity of ATR in the presence and absence of DNA is suppressed by ca eine, a compound which is known to induce loss of checkpoint control. Our results are consistent with the notion that ATR plays a role in monitoring DNA structure and phosphorylation of proteins involved in the DNA damage response pathways.

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“…Genetic and biochemical approaches have identified sensors that detect incompletely replicated or damaged DNA and that stimulate signal transduction pathways that lead to activation of the kinases Chk1 and Chk2/Cds1 (reviewed in Sancar et al, 2004). Both Chk1 and Chk2 can phosphorylate cdc25C on Ser287 (human Ser216), which creates a binding site for 14-3-3 proteins; this is thought to inhibit cdc25C activation and thus the G 2 /M transition (Peng et al, 1997;Sanchez et al, 1997;Kumagai et al, 1998b;Matsuoka et al, 1998;Zeng et al, 1998). The mechanisms by which phosphorylation of this residue and 14-3-3 binding suppress cdc25C's ability to dephosphorylate cdc2, including changes in its subcellular localization in some types of cell cycles (Dalal et al, 1999;Kumagai and Dunphy, 1999;Lopez-Girona et al, 1999;Yang et al, 1999;Graves et al, 2001), are still being worked out.…”

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confidence: 99%

Changes in Regulatory Phosphorylation of Cdc25C Ser287 and Wee1 Ser549 during Normal Cell Cycle Progression and Checkpoint Arrests

Stanford

Ruderman

2005

MBoC

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Entry into mitosis is catalyzed by cdc2 kinase. Previous work identified the cdc2-activating phosphatase cdc25C and the cdc2-inhibitory kinase wee1 as targets of the incomplete replication-induced kinase Chk1. Further work led to the model that checkpoint kinases block mitotic entry by inhibiting cdc25C through phosphorylation on Ser287 and activating wee1 through phosphorylation on Ser549. However, almost all conclusions underlying this idea were drawn from work using recombinant proteins. Here, we report that in the early Xenopus egg cell cycles, phosphorylation of endogenous cdc25C Ser287 is normally high during interphase and shows no obvious increase after checkpoint activation. By contrast, endogenous wee1 Ser549 phosphorylation is low during interphase and increases after activation of either the DNA damage or replication checkpoints; this is accompanied by a slight increase in wee1 kinase activity. Blocking mitotic entry by adding the catalytic subunit of PKA also results in increased wee1 Ser549 phosphorylation and maintenance of cdc25C Ser287 phosphorylation. These results argue that in response to checkpoint activation, endogenous wee1 is indeed a critical responder that functions by repressing the cdc2-cdc25C positive feedback loop. Surprisingly, endogenous wee1 Ser549 phosphorylation is highest during mitosis just after the peak of cdc2 activity. Treatments that block inactivation of cdc2 result in further increases in wee1 Ser549 phosphorylation, suggesting a previously unsuspected role for wee1 in mitosis. INTRODUCTIONEntry into mitosis is initiated by activation of cyclin B/cdc2. Preformed complexes of cyclin B/cdc2 accumulate during interphase, but their activity is repressed by inhibitory phosphorylations on cdc2 at Tyr15 (catalyzed by wee1 and myt1) and Thr14 (catalyzed by myt1). These phosphorylations are removed by the phosphatase cdc25C (reviewed in Berry and Gould, 1996;Lew and Kornbluth, 1996). Early work led to the conclusion that cdc2 and cdc25C activities both increase rapidly during the G 2 /M transition as the result of positive feedback loops between cyclin B/cdc2 and cdc25C, ultimately leading to the full activation of both cdc25C and cyclin B/cdc2 (Izumi et al., 1992;Hoffmann et al., 1993;Izumi and Maller, 1993;Strausfeld et al., 1994). The mechanisms that trigger this abrupt activation are still not well understood (Margolis and Kornbluth, 2004;Perdiguero and Nebreda, 2004).Over the past decade, there has been a large increase in the molecular understanding of how checkpoint pathways become activated, and how they affect the basic cell cycle regulatory machinery. Genetic and biochemical approaches have identified sensors that detect incompletely replicated or damaged DNA and that stimulate signal transduction pathways that lead to activation of the kinases Chk1 and Chk2/Cds1 (reviewed in Sancar et al., 2004). Both Chk1 and Chk2 can phosphorylate cdc25C on Ser287 (human Ser216), which creates a binding site for 14-3-3 proteins; this is thought to inhibit cdc25C activation and thus...

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Replication checkpoint requires phosphorylation of the phosphatase Cdc25 by Cds1 or Chk1

Cited by 319 publications

References 28 publications

Viral infections and cell cycle G2/M regulation

Viral infections and cell cycle G2/M regulation

ATR is a caffeine-sensitive, DNA-activated protein kinase with a substrate specificity distinct from DNA-PK

Changes in Regulatory Phosphorylation of Cdc25C Ser287 and Wee1 Ser549 during Normal Cell Cycle Progression and Checkpoint Arrests

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