Mitotic Exit Function of Polo-like Kinase Cdc5 Is Dependent on Sequential Activation by Cdk1

Rodriguez-Rodriguez, José-Antonio; Moyano, Yolanda; Játiva, Soraya; Queralt, Ethel

doi:10.1016/j.celrep.2016.04.079

Cited by 22 publications

(33 citation statements)

References 55 publications

(76 reference statements)

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“…34 Supporting our observation, a recent study also highlights the role of T238 phosphorylation in regulating the kinase activity of Cdc5 in unperturbed conditions. 31 cdc5-T238A cells do not adapt to one irreparable DSB and uncapped telomeres Cdc5 has been found to promote checkpoint adaptation after one persistent DSB and telomere uncapping. In fact, cdc5-ad cells do not switch Rad53 off and do not re-start cell cycle after one irreparable HO-induced DSB.…”

Section: Resultsmentioning

confidence: 99%

“…1A), has been found phosphorylated by an unknown kinase. 27,31 So far, the functional role of Cdc5 T238 phosphorylation has been poorly studied, because the cdc5-T238A mutation does not affect much cell viability in unperturbed cell cycle ( Fig. 1B and 27 ).…”

Section: Discussionmentioning

confidence: 99%

“…[27][28][29][30] It was also shown that the Cdc5 activity is primed by the CDK1 (Cdc28)-dependent phosphorylation of T242 in the T-loop of the kinase domain. 27,31 In this study, we further characterized the importance to phosphorylate the T238 residue in the T-loop of Cdc5 in S. cerevisiae. We found that this phosphorylation contributes to fully activate Cdc5 kinase activity, without grossly affecting cell growth in unperturbed conditions.…”

Section: Introductionmentioning

confidence: 99%

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Reduced kinase activity of polo kinase Cdc5 affects chromosome stability and DNA damage response inS. cerevisiae

et al. 2016

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Polo-like kinases (PLKs) control several aspects of eukaryotic cell division and DNA damage response. Remarkably, PLKs are overexpressed in several types of cancer, being therefore a marker of bad prognosis. As such, specific PLK kinase activity inhibitors are already used in clinical trials and the regulation of PLK activation is a relevant topic of cancer research. Phosphorylation of threonine residues in the T-loop of the kinase domain is pivotal for PLKs activation. Here, we show that T238A substitution in the T-loop reduces the kinase activity of Cdc5, the only PLK in Saccharomyces cerevisiae, with minor effect on cell growth in unperturbed conditions. However, the cdc5-T238A cells have increased rate of chromosome loss and gross chromosomal rearrangements, indicating altered genome stability. Moreover, the T238A mutation affects timely localization of Cdc5 to the spindle pole bodies and blocks cell cycle restart after one irreparable double-strand break. In cells responding to alkylating agent metylmethane sulfonate (MMS), the cdc5-T238A mutation reduces the phosphorylation of Mus81-Mms4 resolvase and exacerbates the MMS sensitivity of sgs1Δ cells that accumulate Holliday junctions. Of importance, the previously described checkpoint adaptation defective allele, cdc5-ad does not show reduced kinase activity, defective Mms4 phosphorylation and genetic interaction with sgs1Δ. Our data define the importance of regulating Cdc5 activity through T-loop phosphorylation to preserve genome integrity and respond to DNA damage.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reduced kinase activity of polo kinase Cdc5 affects chromosome stability and DNA damage response inS. cerevisiae

et al. 2016

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“…Cdc5 plays a dual role in Cdc14 release as part of both the FEAR and the MEN. Interestingly, recent insights into this process suggest that Cdc5 is sequentially phosphorylated by Clb2-Cdk1 in order to promote the successive waves of Cdc14 release [62]. Cdc14 sequential liberation is of paramount importance during the metaphase-to-anaphase transition for spindle stabilization and elongation, activation of the MEN, mitotic exit, and cytokinesis [45,49,[63][64][65][66] (Figure 1).…”

Section: Cdc14 and The Regulation Of The Cell Cyclementioning

confidence: 99%

The Multiple Roles of the Cdc14 Phosphatase in Cell Cycle Control

Manzano-López

Monje-Casas

2020

IJMS

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The Cdc14 phosphatase is a key regulator of mitosis in the budding yeast Saccharomyces cerevisiae. Cdc14 was initially described as playing an essential role in the control of cell cycle progression by promoting mitotic exit on the basis of its capacity to counteract the activity of the cyclin-dependent kinase Cdc28/Cdk1. A compiling body of evidence, however, has later demonstrated that this phosphatase plays other multiple roles in the regulation of mitosis at different cell cycle stages. Here, we summarize our current knowledge about the pivotal role of Cdc14 in cell cycle control, with a special focus in the most recently uncovered functions of the phosphatase.

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“…Cdc14 is released from the nucleolus by the sequential action of two additional pathways. The FEAR (Cdc Fourteen Early Anaphase Release) pathway promotes the early release of Cdc14 through the phosphorylation of Cif1/Net1 and Cdc14 [28][29][30][31][32][33]. Late in anaphase, the Mitotic Exit Network (MEN) keeps Cdc14 in its released state, allowing the de-phosphorylation of additional substrates, important for the full termination of mitosis and cytokinesis [34,35].…”

Section: Introductionmentioning

confidence: 99%

The Cdc14 phosphatase controls resolution of recombination intermediates and crossover formation during meiosis

Alonso-Ramos

Álvarez-Melo

Strouhalova

et al. 2019

Preprint

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Meiotic defects derived from incorrect DNA repair during gametogenesis can lead to mutations, aneuploidies and infertility. Effective and coordinated resolution of meiotic recombination intermediates is necessary to accomplish both rounds of successful chromosome segregation. Cdc14 is an evolutionarily conserved dual-specificity phosphatase required for mitotic exit and meiotic progression. Mutations that inactivate the phosphatase lead to meiotic failure. Here, we have identified previously unseen roles of Cdc14 in ensuring correct meiotic recombination. We found that aberrant recombination intermediates accumulate during prophase I when Cdc14 protein levels are drastically reduced. Furthermore, Cdc14 plays a role in suppressing the formation of non-allelic (ectopic) recombination products. We also demonstrate that Cdc14 is required for correct sister chromatid disjunction during the second meiotic divisions. Finally, Cdc14 is required in meiosis for the timely activation of the conserved Holliday Junction resolvase, Yen1/GEN1 in anaphase II. Based on these new findings we propose an early function for Cdc14 in meiotic recombination independent of its later roles during anaphase I/II. 2 Author SummaryMeiotic recombination is fundamental for sexual reproduction, effective and coordinated resolution of recombination intermediates is critical for correct chromosome segregation. Homologous recombination is initiated by the introduction of programmed DSBs followed by the formation of complex branched DNA intermediates, including double Holliday Junctions (dHJs). These recombination intermediates are eventually repaired into crossover or non-crossover products. In some cases, unresolved recombination intermediates, or toxic repair products, might persist until the metaphase to anaphase transition, requiring of a subset of late-acting repairing enzymes to process them.Unrestrained activity of these enzymes might equally put at risk the genome integrity, thus, several layers of regulation tightly control them. For example, in budding yeast meiosis, Yen1/GEN1 is only activated during the second meiotic division, although how it is activated is unknown. Here, we have identified the requirement of the Cdc14 phosphatase for the timely activation of Yen1 during the second division in meiotic cells. Additionally, we have been able to identify a previously undescribed role of Cdc14 in meiotic recombination. Strikingly, we found that levels of aberrant recombination intermediates accumulate during prophase I in cdc14 meiotic deficient cells. Furthermore, in the absence of Cdc14 activity, there is an increase of ectopic recombination products, indicating that Cdc14 plays a direct role in monitoring meiotic DSB repair, possibly in a way independent of Yen1. Such accumulation of persistent recombination intermediates is not sensed by the checkpoint machinery at the end of prophase I, and their abnormal accumulation in cdc14 meiotic cells likely contribute to the missegregation problems observed during the second meiotic division.

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Mitotic Exit Function of Polo-like Kinase Cdc5 Is Dependent on Sequential Activation by Cdk1

Cited by 22 publications

References 55 publications

Reduced kinase activity of polo kinase Cdc5 affects chromosome stability and DNA damage response inS. cerevisiae

Reduced kinase activity of polo kinase Cdc5 affects chromosome stability and DNA damage response inS. cerevisiae

The Multiple Roles of the Cdc14 Phosphatase in Cell Cycle Control

The Cdc14 phosphatase controls resolution of recombination intermediates and crossover formation during meiosis

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