Centrosome-Dependent Bypass of the DNA Damage Checkpoint by the Polo Kinase Cdc5

Ratsima, Hery; Serrano, Diego; Pascariu, Mirela; D’Amours, Damien

doi:10.1016/j.celrep.2016.01.014

Cited by 18 publications

(37 citation statements)

References 55 publications

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“…[44][45][46][47] Therefore, we can speculate that unprocessed HJs accumulate in the sgs1D cdc5-T238A cells, leading to aberrant chromosome segregation and loss, increase GCRs and hyper-sensitivity to MMS. Most important, our results in Figure 6 on genome rearrangement and chromosome stability, taken together with the recently involvement of Cdc5 in maintaining genome ploidy, 42 further support Cdc5 as key factor to preserve genome integrity.…”

Section: Discussionsupporting

confidence: 77%

“…[17][18][19] Moreover, a clear link between the localization of Cdc5 at centrosomes and checkpoint adaptation to persistent DNA damage and spindle depolarization has been recently established. 42,58 Of interest, we found that the Cdc5-T238A protein variant relocalizes to SPBs with several hours of delay, according to the prolonged cell cycle block after one irreparable DSB (Fig. 4).…”

Section: Discussionmentioning

confidence: 94%

“…Intriguingly, our analysis suggest that misregulation at SPBs may contribute to prevent cell cycle re-start by checkpoint adaptation in cdc5-T238A and cdc5-ad cells, as recently shown in a separate class of cdc5 alleles, carrying mutations in the polo box domain. 42…”

Section: Resultsmentioning

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: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 94%

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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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“…Cells carrying the cdc5-ad allele and challenged by an unrepairable DNA damage stay arrested in G2/M and maintain Rad53 in an activated state (Pellicioli et al 2001). Other recently identified adaptation mutants of CDC5 (cdc5-16 and cdc5-T238A) have also contributed to the dissection of Cdc5's role in adaptation (Ratsima et al 2011;Ratsima et al 2016;Rawal et al 2016). However, despite its central role in adaptation, the exact mechanisms by which Cdc5 exerts its function and which Cdc5 targets are affected in response to DNA damage are still unclear (Hu et al 2001;Zhang et al 2009;Donnianni et al 2010;Dotiwala et al 2010;Schleker et al 2010;Vidanes et al 2010;Valerio-Santiago et al 2013;Ratsima et al 2016;Rawal et al 2016;Botchkarev et al 2017).…”

Section: Dna Damage Checkpoint and Adaptationmentioning

confidence: 99%

Adaptation in replicative senescence: a risky business

Coutelier

2019

Curr Genet

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Cell proliferation is tightly regulated to avoid propagating DNA damage and mutations, which can lead to pathologies such as cancer. To ensure genome integrity, cells activate the DNA damage checkpoint in response to genotoxic lesions to block cell cycle progression. This surveillance mechanism provides time to repair the damage before resuming cell cycle with an intact genome. When the damage is not repaired, cells can, in some conditions, override the cell cycle arrest and proceed with proliferation, a phenomenon known as adaptation to DNA damage. A subpopulation of adapted cells might eventually survive, but only at the cost of extensive genome instability. How and in which context adaptation operates the trade-off between survival and genome stability is a fascinating question. After a brief review of the current knowledge on adaptation to DNA damage in budding yeast, we will discuss a new role of adaptation in the context of telomerase-negative cells and replicative senescence. We highlight the idea that, in all settings studied so far, survival through adaptation is a double-edged sword as it comes with increased genomic instability.

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“…We have previously shown that mutations affecting the phosphopeptide-binding activity of the polo-box domain of Cdc5 are tolerated in yeast as they generate viable alleles that are not associated with strong proliferation defects 35 . However, these alleles show a striking misregulation of cell cycle checkpoints and are defective in their maintenance of genome stability 35,36 . In light of these observations, we wanted to assess the physiological impact of mutations affecting the hydrophobic pocket of the polo-box.…”

mentioning

confidence: 99%

Distinct surfaces on Cdc5/PLK Polo-box domain orchestrate combinatorial substrate recognition during cell division

Almawi

Langlois-Lemay

Boulton

et al. 2020

Sci Rep

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Polo-like kinases (Plks) are key cell cycle regulators. They contain a kinase domain followed by a polobox domain that recognizes phosphorylated substrates and enhances their phosphorylation. The regulatory subunit of the Dbf4-dependent kinase complex interacts with the polo-box domain of Cdc5 (the sole plk in Saccharomyces cerevisiae) in a phosphorylation-independent manner. We have solved the crystal structures of the polo-box domain of Cdc5 on its own and in the presence of peptides derived from Dbf4 and a canonical phosphorylated substrate. The structure bound to the Dbf4-peptide reveals an additional density on the surface opposite to the phospho-peptide binding site that allowed us to propose a model for the interaction. We found that the two peptides can bind simultaneously and non-competitively to the polo-box domain in solution. Furthermore, point mutations on the surface opposite to the phosphopeptide binding site of the polo-box domain disrupt the interaction with the Dbf4 peptide in solution and cause an early anaphase arrest phenotype distinct from the mitotic exit defect typically observed in cdc5 mutants. Collectively, our data illustrates the importance of noncanonical interactions mediated by the polo-box domain and provide key mechanistic insights into the combinatorial recognition of substrates by Polo-like kinases. Processes that drive mitotic progression are under strict cellular regulation to ensure the faithful propagation of newly replicated genetic material. Cellular defects that arise during mitosis-such as sister chromatid mis-alignment or spindle pole mis-positioning-can lead to chromosome segregation defects and give rise to polyploid and aneuploid daughter cells 1-3. It is during these events that the cell activates signaling cascades known as checkpoints to inhibit mitotic processes 4. Misregulation of mitotic checkpoints gives cells a proliferative advantage-one of the hallmarks of carcinogenesis 3,5. A conserved family of kinases known as Polo-like kinases (Plks) control mitotic events 6. Plks function in mitotic entry, spindle pole dynamics, chromosome condensation 7 , sister-chromatid segregation 8 , and cytokinesis 2,6,9. Plk1 is upregulated in multiple human tumors and, therefore, has become an attractive anti-cancer target 10,11. The structural similarity with other cellular kinases, however, has limited the potential of inhibiting Plk1 due to off-target effects. Some of the most selective drugs against Plk1 also inhibit Plk2 and Plk3 with similar potency 12,13. Therefore, targeting interactions that regulate kinase activity provide a promising approach to specifically target Plk1. Much of our understanding of Plk1 comes from Cdc5, the sole Plk in budding yeast 4,14,15. Cdc5 promotes the release of Cdc14 from the nucleolus and regulates the mitotic exit network (MEN) 9,16-18 as well as cytokinesis 19-21. Full release of Cdc14 leads to the downstream activation of the anaphase promoting complex, cyclin destruction, mitotic spindle disassembly, and displacement of the septin ri...

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Centrosome-Dependent Bypass of the DNA Damage Checkpoint by the Polo Kinase Cdc5

Cited by 18 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

Adaptation in replicative senescence: a risky business

Distinct surfaces on Cdc5/PLK Polo-box domain orchestrate combinatorial substrate recognition during cell division

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