Downregulation of Wip1 phosphatase modulates the cellular threshold of DNA damage signaling in mitosis

Macůrek, Libor; Benada, Jan; Müllers, Erik; Halim, Vincentius A.; Krejčíková, Kateřina; Burdová, Kamila; Pecháčková, Soňa; Hodný, Zdeněk; Lindqvist, Arne; Medema, René H.; Bártek, Jiří

doi:10.4161/cc.23057

Cited by 49 publications

(44 citation statements)

References 60 publications

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“…We found that Wip1 protein but not its mRNA in the hippocampus is down-regulated in response to CUMS. Our result is consistent with the previous studies in which Wip1 protein was downregulated in response to DNA damage response (Macurek et al, 2012;Vaz and Ramadan, 2013). Although a rapid (several hours) upregulation of Wip1 mRNA was consistently observed in response to a number of stresses such as ultraviolet radiation and ionizing radiation (Takekawa et al, 2000;Demidov et al, 2006;Dayaram et al, 2013), no change of Wip1 mRNA is detected after 28 days of CUMS.…”

Section: Discussionsupporting

confidence: 94%

Mice deficient for wild-type p53-induced phosphatase 1 display elevated anxiety- and depression-like behaviors

Ruan

Zhou

et al. 2015

Neuroscience

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Section: Discussionsupporting

confidence: 94%

Mice deficient for wild-type p53-induced phosphatase 1 display elevated anxiety- and depression-like behaviors

Ruan

Zhou

et al. 2015

Neuroscience

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“…Increased sensitivity of mitotic cells to ionizing radiation probably reflects the degradation of PPM1D phosphatase (also known as Wip1) we previously reported. 24 In contrast, 53BP1 was excluded from the chromatin in mitotic cells and did not colocalize with gH2AX in mitotic cells after irradiation. We hypothesized that distinct behavior of 53BP1 in interphase and mitotic cells might be at least in part caused by its posttranslational modifications and thus we aimed to investigate the impact of mitotic posttranslational modifications on 53BP1 function.…”

Section: Bp1 Is Phosphorylated By Cdk1 and Plk1 In Mitosismentioning

confidence: 92%

“…46,47 The ability of ATM to respond even to such minimal extent of DNA damage during mitosis may be facilitated by APC cdc20 -dependent degradation of the opposing phosphatase Wip1 during mitosis. 24 Although ATM is activated normally during mitosis, the downstream events in the DDR that depend on chromatin ubiquitination are supressed in mitosis. 19,21 Here, we have shown that mitotic kinases Cdk1 and Plk1 phosphorylate 53BP1 within its UDR domain, block its interaction with ubiquitinated chromatin and interfere with its function in DNA repair.…”

Section: Discussionmentioning

confidence: 99%

Polo-like kinase 1 inhibits DNA damage response during mitosis

et al. 2015

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Abbreviations: 53BP1, p53 binding protein 1; ATM, ataxia telangiectasia mutated kinase; BRCA1, breast cancer type 1 susceptibility protein; Cdk, cyclin dependent kinase; DDR, DNA damage response; Plk1, Polo-like kinase 1; H2AX, histone variant H2AX; IR -ionizing radiation; MDC1, mediator of DNA damage checkpoint protein 1; NCS -neocarzinostatin; NZ -nocodazole; PTIP, PAX transactivation activation domain-interacting protein; RIF1, Rap1-interacting factor 1 homolog; RNAi, RNA interference; RNF8, RING finger protein 8; RNF168, RING finger protein 168.In response to genotoxic stress, cells protect their genome integrity by activation of a conserved DNA damage response (DDR) pathway that coordinates DNA repair and progression through the cell cycle. Extensive modification of the chromatin flanking the DNA lesion by ATM kinase and RNF8/RNF168 ubiquitin ligases enables recruitment of various repair factors. Among them BRCA1 and 53BP1 are required for homologous recombination and nonhomologous end joining, respectively. Whereas mechanisms of DDR are relatively well understood in interphase cells, comparatively less is known about organization of DDR during mitosis. Although ATM can be activated in mitotic cells, 53BP1 is not recruited to the chromatin until cells exit mitosis. Here we report mitotic phosphorylation of 53BP1 by Plk1 and Cdk1 that impairs the ability of 53BP1 to bind the ubiquitinated H2A and to properly localize to the sites of DNA damage. Phosphorylation of 53BP1 at S1618 occurs at kinetochores and in cytosol and is restricted to mitotic cells. Interaction between 53BP1 and Plk1 depends on the activity of Cdk1. We propose that activity of Cdk1 and Plk1 allows spatiotemporally controlled suppression of 53BP1 function during mitosis.

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“…Although kinase(s) responsible for all phosphorylation events are not currently known, phosphomimetic mutations of 7 phospho-acceptor sites within Wip1 completely abolished its phosphatase activity. 48 This work increased understanding of Wip1 regulation and provided insight that regulation of Wip1 phosphatase activity utilizes mechanisms independent of changes in its protein levels.…”

Section: Discussionmentioning

confidence: 99%

LZAP is a novel Wip1 binding partner and positive regulator of its phosphatase activity in vitro

Wamsley

Issaeva

et al. 2016

Cell Cycle

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The phosphatase Wip1 attenuates the DNA damage response (DDR) by removing phosphorylation marks from a number of DDR proteins (p53, MDM2, Chk1/2, p38). Wip1 also dephosphorylates and inactivates RelA. Notably, LZAP, a putative tumor suppressor, has been linked to dephosphorylation of several of these substrates, including RelA, p38, Chk1, and Chk2. LZAP has no known catalytic activity or functional motifs, suggesting that it exerts its effects through interaction with other proteins. Here we show that LZAP binds Wip1 and stimulates its phosphatase activity. LZAP had been previously shown to bind many Wip1 substrates (RelA, p38, Chk1/2), and our results show that LZAP also binds the previously identified Wip1 substrate, MDM2. This work identifies 2 novel Wip1 substrates, ERK1 and HuR, and demonstrates that HuR is a binding partner of LZAP. Pleasingly, LZAP potentiated Wip1 catalytic activity toward each substrate tested, regardless of whether full-length substrates or phosphopeptides were utilized. Since this effect was observed on ERK1, which does not bind LZAP, as well as for each of 7 peptides tested, we hypothesize that LZAP binding to the substrate is not required for this effect and that LZAP directly binds Wip1 to augment its phosphatase activity.

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Downregulation of Wip1 phosphatase modulates the cellular threshold of DNA damage signaling in mitosis

Cited by 49 publications

References 60 publications

Mice deficient for wild-type p53-induced phosphatase 1 display elevated anxiety- and depression-like behaviors

Mice deficient for wild-type p53-induced phosphatase 1 display elevated anxiety- and depression-like behaviors

Polo-like kinase 1 inhibits DNA damage response during mitosis

LZAP is a novel Wip1 binding partner and positive regulator of its phosphatase activity in vitro

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