Polo-like kinase 4 phosphorylates Chk2

Petrinac, Steve; Ganuelas, Melissa L.; Bonni, Sepal; Nantais, Jordan; Hudson, John W.

doi:10.4161/cc.8.2.7355

Cited by 15 publications

(15 citation statements)

References 10 publications

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“…Here we found that high levels of Cdc5 separately affected Mec1 signaling and DSB processing, leading us to speculate that Cdc5 may regulate multiple targets in response to DNA damage, including factors phosphorylated by CDK1. In support of such hypothesis, Plks phosphorylate, in vertebrates, several proteins involved in various aspects of the DNA damage response, such as FANCM [25], Claspin [21]–[24], Chk2 [26]–[28], MCM5 [76], MCM7 [77] and others. Moreover, our findings on the functional role of Cdc5 in responding to a DSB in yeast rise the possibility that Plks may also regulate CtIP.…”

Section: Resultsmentioning

confidence: 89%

“…In vertebrates, polo kinases regulate the DNA damage checkpoint response by affecting the signal transduction pathway at different levels; interestingly, Chk2, the homologue of Rad53 in human cells, interacts with and is phosphorylated by the polo kinases Plk1, Plk3 and Plk4 [26]–[28].…”

Section: Resultsmentioning

confidence: 99%

“…They phosphorylate Claspin [21]–[24], a Chk1 kinase regulator, and the Fanconi-Anemia protein FANCM [25], promoting their degradation and checkpoint inactivation. Further, Plk1, Plk3 and Plk4 interact with and phosphorylate Chk2, the ortholog of Rad53 in human cells, likely influencing its activity [26]–[28]. Interestingly, yeast Cdc5 is phosphorylated and inhibited in a Mec1- and Rad53-dependent manner [29], and several studies indicate that in mammals Plk1 activity is inhibited by ATM/ATR-signaling in response to DNA damage [30]–[33].…”

Section: Introductionmentioning

confidence: 99%

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Elevated Levels of the Polo Kinase Cdc5 Override the Mec1/ATR Checkpoint in Budding Yeast by Acting at Different Steps of the Signaling Pathway

et al. 2010

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Checkpoints are surveillance mechanisms that constitute a barrier to oncogenesis by preserving genome integrity. Loss of checkpoint function is an early event in tumorigenesis. Polo kinases (Plks) are fundamental regulators of cell cycle progression in all eukaryotes and are frequently overexpressed in tumors. Through their polo box domain, Plks target multiple substrates previously phosphorylated by CDKs and MAPKs. In response to DNA damage, Plks are temporally inhibited in order to maintain the checkpoint-dependent cell cycle block while their activity is required to silence the checkpoint response and resume cell cycle progression. Here, we report that, in budding yeast, overproduction of the Cdc5 polo kinase overrides the checkpoint signaling induced by double strand DNA breaks (DSBs), preventing the phosphorylation of several Mec1/ATR targets, including Ddc2/ATRIP, the checkpoint mediator Rad9, and the transducer kinase Rad53/CHK2. We also show that high levels of Cdc5 slow down DSB processing in a Rad9-dependent manner, but do not prevent the binding of checkpoint factors to a single DSB. Finally, we provide evidence that Sae2, the functional ortholog of human CtIP, which regulates DSB processing and inhibits checkpoint signaling, is regulated by Cdc5. We propose that Cdc5 interferes with the checkpoint response to DSBs acting at multiple levels in the signal transduction pathway and at an early step required to resect DSB ends.

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Section: Resultsmentioning

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Elevated Levels of the Polo Kinase Cdc5 Override the Mec1/ATR Checkpoint in Budding Yeast by Acting at Different Steps of the Signaling Pathway

et al. 2010

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“…In mice, Plk4 is haploinsufficient for tumour suppression, while in humans, loss of heterozygosity (LOH) for the Plk4 gene was found in 60% of a small sample of human hepatocellular carcinomas (HCC) cases[7]. The increased rate of tumourigenesis is likely related to the generation of aneuploidy, as altered Plk4 levels result in abnormal centrosome numbers [8], furthermore Plk4 may also play a key role in a DNA damage response pathway consistent with its phosphorylation of p53 [7], and Chk2 [9]. In general, overexpression of Plk1 is typically considered to be oncogenic in nature while the remaining Plks likely function as tumour suppressors.…”

Section: Introductionmentioning

confidence: 99%

Aberrant methylation of Polo-like kinase CpG islands in Plk4 heterozygous mice

et al. 2011

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BackgroundHepatocellular carcinoma (HCC), one of the most common cancers world-wide occurs twice as often in men compared to women. Predisposing conditions such as alcoholism, chronic viral hepatitis, aflatoxin B1 ingestion, and cirrhosis all contribute to the development of HCC.MethodsWe used a combination of methylation specific PCR and bisulfite sequencing, qReal-Time PCR (qPCR), and Western blot analysis to examine epigenetic changes for the Polo-like kinases (Plks) during the development of hepatocellular carcinoma (HCC) in Plk4 heterozygous mice and murine embryonic fibroblasts (MEFs).ResultsHere we report that the promoter methylation of Plk4 CpG islands increases with age, was more prevalent in males and that Plk4 epigenetic modification and subsequent downregulation of expression was associated with the development of HCC in Plk4 mutant mice. Interestingly, the opposite occurs with another Plk family member, Plk1 which was typically hypermethylated in normal liver tissue but became hypomethylated and upregulated in liver tumours. Furthermore, upon alcohol exposure murine embryonic fibroblasts exhibited increased Plk4 hypermethylation and downregulation along with increased centrosome numbers and multinucleation.ConclusionsThese results suggest that aberrant Plk methylation is correlated with the development of HCC in mice.

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“…Additionally, PLK4 has been shown to phosphorylate p53 and CHK2, both of which are important components of the DNA damage response (Ko et al 5 2005;Petrinac et al 2009). PLK4's role in other cellular compartments is less clear.…”

Section: Introductionmentioning

confidence: 98%

Developmental role ofplk4inXenopus laevisandDanio rerio:implications for Seckel Syndrome

Rapchak

Patel

Hudson

et al. 2015

Biochem. Cell Biol.

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The polo-like kinases are a family of conserved serine/threonine kinases that play multiple roles in regulation of the cell cycle. Unlike its four other family members, the role of Plk4 in embryonic development has not been well characterized. In mice, Plk4(-)(/)(-) embryos arrest at E7.5, just prior to the initiation of somitogenesis. This has led to the hypothesis that Plk4 expression may be essential to somitogenesis. Recently characterized human mutations lead to Seckel Syndrome. Riboprobe in situ hybridization revealed that plk4 is ubiquitously expressed during early stages of development of Xenopus and Danio; in later stages, expression in frogs restricts to somites as well as eye, otic vesicle, and branchial arch, and brain. Expression patterns in fish remain ubiquitous. Both somite and eye development require planar cell polarity, and disruption of plk4 function in frog by means of morpholino-mediated translational knockdown yields orientational disorganization of both these structures. These results provide the first steps in defining a new role for plk4 in organogenesis and implies a role in planar cell polarity, segmentation, and in recently described PLK4 mutations in human.

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Polo-like kinase 4 phosphorylates Chk2

Cited by 15 publications

References 10 publications

Elevated Levels of the Polo Kinase Cdc5 Override the Mec1/ATR Checkpoint in Budding Yeast by Acting at Different Steps of the Signaling Pathway

Elevated Levels of the Polo Kinase Cdc5 Override the Mec1/ATR Checkpoint in Budding Yeast by Acting at Different Steps of the Signaling Pathway

Aberrant methylation of Polo-like kinase CpG islands in Plk4 heterozygous mice

Developmental role ofplk4inXenopus laevisandDanio rerio:implications for Seckel Syndrome

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