PP2C Phosphatases Ptc2 and Ptc3 Are Required for DNA Checkpoint Inactivation after a Double-Strand Break

Leroy, C.; Lee, Sang Eun; Vaze, Moreshwar B.; Ochsenbien, Françoise; Guérois, Raphaël; Haber, James E.; Marsolier-Kergoat, Marie Claude

doi:10.1016/s1097-2765(03)00058-3

Cited by 179 publications

(158 citation statements)

References 37 publications

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“…It has been reported that Ptc2 and Ptc3, two members of the PP2C family, bind to Rad53 and inactivate Rad53-dependent pathways in S. cerevisiae. 21 Considering our results, it is likely that Ptc2 and Ptc3 inactivate Rad53 by dephosphorylating it. Furthermore, we provide evidence suggesting that Wip1 may (Figures 4 and 5).…”

Section: Antagonistic Effect Of Wip1 On Chk2-dependent Apoptosismentioning

confidence: 62%

“…20 On the other hand, in Saccharomyces cerevisiae, the type 2C protein phosphatases (PP2C), Ptc2 and Ptc3, bind to Rad53, the S. cerevisiae orthologue of Chk2, and inactivate Rad53 presumably by dephosphorylating Rad53, leading to checkpoint inactivation upon a DNA double-strand break. 21 Thus, it can be assumed that protein phosphatases may mediate the termination of DNA damage-induced cell-cycle checkpoint arrest to restart cell cycle by dephosphorylating and inactivating checkpoint kinases. Despite the high degree of conservation between cell-cycle checkpoint in yeast and mammals, it remains unknown whether or not protein phosphatases are involved in the termination of DNA damage-induced cell-cycle checkpoint arrest in mammals.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase

et al. 2005

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The antioncogenic Chk2 kinase plays a crucial role in DNA damage-induced cell-cycle checkpoint regulation. Here we show that Chk2 associates with the oncogenic protein Wip1 (wild-type p53-inducible phosphatase 1) (PPM1D), a p53-inducible protein phosphatase. Phosphorylation of Chk2 at threonine68 (Thr68), a critical event for Chk2 activation, which is normally induced by DNA damage or overexpression of Chk2, is inhibited by expression of wild-type (WT), but not a phosphatase-deficient mutant (D314A) of Wip1 in cultured cells. Furthermore, an in vitro phosphatase assay revealed that Wip1 (WT), but not Wip1 (D314A), dephosphorylates Thr68 on phosphorylated Chk2 in vitro, resulting in the inhibition of Chk2 kinase activity toward glutathione S-transferase-Cdc25C. Moreover, inhibition of Wip1 expression by RNA interference results in abnormally sustained Thr68 phosphorylation of Chk2 and increased susceptibility of cells in response to DNA damage, indicating that Wip1 acts as a negative regulator of Chk2 in response to DNA damage.

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Section: Antagonistic Effect Of Wip1 On Chk2-dependent Apoptosismentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase

et al. 2005

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“…We previously showed that the Ptc2 and Ptc3 phosphatases in budding yeast interact with and downregulate the Rad53 checkpoint kinase after a DNA DSB (Leroy et al, 2003). Ptc2 and Ptc3 belong to the PP2C family of protein phosphatases.…”

Section: Wip1 Selectively Reverses the Action Of Atm On Chk2mentioning

confidence: 99%

“…Rad53 is the budding yeast ortholog of Chk2. Previously, we showed that two type 2C protein phosphatases (PP2C), Ptc2 and Ptc3, were required for inactivation of the Rad53 DNA damage checkpoint during adaptation and recovery from a DNA DSB in Saccharomyces cerevisiae (Leroy et al, 2003). In this study, we sought to test the conservation of this pathway by looking for an orthologous human PP2C phosphatase able to inactivate Chk2.…”

Section: Introductionmentioning

confidence: 99%

The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase

et al. 2006

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We previously demonstrated that type 2C protein phosphatases (PP2C) Ptc2 and Ptc3 are required for DNA checkpoint inactivation after DNA double-strand break repair or adaptation in Saccharomyces cerevisiae. Here, we show the conservation of this pathway in mammalian cells. In response to DNA damage, ataxia telangiectasia mutated (ATM) phosphorylates the Chk2 tumour suppressor kinase at threonine 68 (Thr68), allowing Chk2 kinase dimerization and activation by autophosphorylations in the T-loop. The oncogenic protein Wip1, a PP2C phosphatase, binds Chk2 and dephosphorylates phosphoThr68. Consequently, Wip1 opposes Chk2 activation by ATM after ionizing irradiation of cells. In HCT15 colorectal cancer cells corrected for functional Chk2 activity, Wip1 overexpression suppressed the contribution of Chk2 to the G2/M DNA damage checkpoint. These results indicate that Wip1 is one of the phosphatases regulating the activity of Chk2 in response to DNA damage.

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“…Although the process of recovery is conserved in budding yeast, the sole member of the PLK family in this organism, Cdc5, and some of the homologs of the Plk1 substrates mentioned above are not involved in the recovery process in this organism (Jin and Wang 2006;Vaze et al 2002). Additional mechanisms may be in place in lower eukaryotes to promote recovery after DNA repair is completed (Guillemain et al 2007;Leroy et al 2003;O'Neill et al 2007). …”

Section: Cellular Recovery From Dna Damagementioning

confidence: 99%

When genome integrity and cell cycle decisions collide: roles of polo kinases in cellular adaptation to DNA damage

Serrano

D’Amours

2014

Syst Synth Biol

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The drive to proliferate and the need to maintain genome integrity are two of the most powerful forces acting on biological systems. When these forces enter in conflict, such as in the case of cells experiencing DNA damage, feedback mechanisms are activated to ensure that cellular proliferation is stopped and no further damage is introduced while cells repair their chromosomal lesions. In this circumstance, the DNA damage response dominates over the biological drive to proliferate, and may even result in programmed cell death if the damage cannot be repaired efficiently. Interestingly, the drive to proliferate can under specific conditions overcome the DNA damage response and lead to a reactivation of the proliferative program in checkpoint-arrested cells. This phenomenon is known as adaptation to DNA damage and is observed in all eukaryotic species where the process has been studied, including normal and cancer cells in humans. Polo-like kinases (PLKs) are critical regulators of the adaptation response to DNA damage and they play key roles at the interface of cell cycle and checkpoint-related decisions in cells. Here, we review recent progress in defining the specific roles of PLKs in the adaptation process and how this conserved family of eukaryotic kinases can integrate the fundamental need to preserve genomic integrity with effective cellular proliferation.

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PP2C Phosphatases Ptc2 and Ptc3 Are Required for DNA Checkpoint Inactivation after a Double-Strand Break

Cited by 179 publications

References 37 publications

Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase

Regulation of the antioncogenic Chk2 kinase by the oncogenic Wip1 phosphatase

The Wip1 phosphatase (PPM1D) antagonizes activation of the Chk2 tumour suppressor kinase

When genome integrity and cell cycle decisions collide: roles of polo kinases in cellular adaptation to DNA damage

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