Coordination of Chromatid Separation and Spindle Elongation by Antagonistic Activities of Mitotic and S-Phase CDKs

Liang, Fushun; Richmond, Daniel; Wang, Yanchang

doi:10.1371/journal.pgen.1003319

Cited by 12 publications

(12 citation statements)

References 47 publications

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“…We found that a group of Cdk1 targets that are dephosphorylated in anaphase, Fin1, Spc110, and Cnn1 (Woodbury & Morgan, 2007; Bock et al , 2012; Liang et al , 2013) contain Clb5‐specific NLxxxL motifs (Fig 7D). We analyzed the cyclin specificity of phosphorylation of these substrates and confirmed that, as predicted, Fin1, Spc110, and Cnn1 are most efficiently phosphorylated by Clb5‐Cdk1, when compared with Clb3‐ and Clb2‐Cdk1 (Fig 7E).…”

Section: Resultsmentioning

confidence: 86%

A new linear cyclin docking motif that mediates exclusively S‐phase CDK‐specific signaling

et al. 2020

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Cyclin‐dependent kinases (CDKs), the master regulators of cell division, are activated by different cyclins at different cell cycle stages. In addition to being activators of CDKs, cyclins recognize various linear motifs to target CDK activity to specific proteins. We uncovered a cyclin docking motif, NLxxxL, that contributes to phosphorylation‐dependent degradation of the CDK inhibitor Far1 at the G1/S stage in the yeast Saccharomyces cerevisiae. This motif is recognized exclusively by S‐phase CDK (S‐CDK) Clb5/6‐Cdc28 and is considerably more potent than the conventional RxL docking motif. The NLxxxL and RxL motifs were found to overlap in some target proteins, suggesting that cyclin docking motifs can evolve to switch from one to another for fine‐tuning of cell cycle events. Using time‐lapse fluorescence microscopy, we show how different docking connections temporally control phosphorylation‐driven target degradation. This also revealed a differential function of the phosphoadaptor protein Cks1, as Cks1 docking potentiated degron phosphorylation of RxL‐containing but not of NLxxxL‐containing substrates. The NLxxxL motif was found to govern S‐cyclin‐specificity in multiple yeast CDK targets including Fin1, Lif1, and Slx4, suggesting its wider importance.

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Section: Resultsmentioning

confidence: 86%

A new linear cyclin docking motif that mediates exclusively S‐phase CDK‐specific signaling

et al. 2020

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“…Previous work showed that Net1 phosphorylation by Clb2/Cdk1 triggers Cdc14 release, and mutation of the six phosphorylation sites ( net1-6Cdk ) blocks FEAR activation and the premature Cdc14 release in cdc55 Δ mutants (Azzam et al, 2004; Liang et al, 2013). To further assess if the sensitivity of cdc55 Δ swe1 Δ cells to syntelic attachment is due to hyperactive FEAR, we compared the growth of cdc55 Δ swe1 Δ and cdc55 Δ swe1 Δ net1-6Cdk cells overexpressing CIK1-CC.…”

Section: Resultsmentioning

confidence: 99%

“…Deletion of PP2A regulatory gene CDC55 leads to premature Cdc14 release (Liang et al, 2009; Wang and Ng, 2006). FEAR-dependent Cdc14 release specifically reverses the phosphorylation imposed by S-phase CDK to facilitate anaphase progression (Jin et al, 2008; Liang et al, 2013). Fin1 is a verified S-phase CDK substrate (Loog and Morgan, 2005), and its phosphorylation promotes its interaction with 14-3-3 proteins, Bmh1 and Bmh2, which prevents the kinetochore association of Fin1 (Akiyoshi et al, 2009; Mayordomo and Sanz, 2002).…”

Section: Introductionmentioning

confidence: 99%

Fin1-PP1 Helps Clear Spindle Assembly Checkpoint Protein Bub1 from Kinetochores in Anaphase

et al. 2016

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The spindle assembly checkpoint (SAC) monitors chromosome attachment defects and the assembly of SAC proteins at kinetochores is essential for its activation, but the SAC disassembly process remains unknown. We found that deletion of a 14-3-3 protein, Bmh1, or hyper-activation of FEAR (Cdc14 Early Anaphase Release) allows premature SAC silencing in budding yeast, which depends on a kinetochore protein Fin1 that forms a complex with protein phosphatase PP1. Previous works suggest that FEAR-dependent Fin1 dephosphorylation promotes Bmh1-Fin1 dissociation, which enables kinetochore recruitment of Fin1-PP1. We found persistent kinetochore association of SAC protein Bub1 in fin1Δ mutants after anaphase entry. Therefore, we revealed a mechanism that clears SAC proteins from kinetochores. After anaphase entry, FEAR activation promotes kinetochore enrichment of Fin1-PP1, resulting in SAC disassembly at kinetochores. This mechanism is required for efficient SAC silencing after SAC being challenged, and untimely Fin1-kinetochore association causes premature SAC silencing and chromosome missegregation.

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“…At lower temperature, however, pds1Δ cells are viable but chromosome loss is frequent and many cells cannot form colonies (Yamamoto et al. , 1996a; Liang et al. , 2013).…”

Section: Resultsmentioning

confidence: 99%

Characterization of a novel separase-interacting protein and candidate new securin, Eip1p, in the fungal pathogen Candida albicans

Sparapani

Bachewich

2019

MBoC

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Proper chromosome segregation is crucial for maintaining genomic stability and dependent on separase, a conserved and essential cohesin protease. Securins are key regulators of separases, but remain elusive in many organisms due to sequence divergence. Here, we demonstrate that the separase homologue Esp1p in the ascomycete Candida albicans, an important pathogen of humans, is essential for chromosome segregation . However, C. albicans lacks a sequence homologue of securins found in model ascomycetes. We sought a functional homologue through identifying Esp1p interacting factors. Affinity purification of Esp1p and mass spectrometry revealed Esp1p-Interacting Protein1 (Eip1p)/Orf19.955p, an uncharacterized protein specific to Candida species. Functional analyses demonstrated that Eip1p is important for chromosome segregation but not essential, and modulated in an APCCdc20-dependent manner, similar to securins. Eip1p is strongly enriched in response to methyl methanesulfate (MMS) or hydroxyurea (HU) treatment, and its depletion partially suppresses an MMS or HU-induced metaphase block. Further, Eip1p depletion reduces Mcd1p/Scc1p, a cohesin subunit and separase target. Thus, Eip1p may function as a securin. However, other defects in Eip1p-depleted cells suggest additional roles. Overall, the results introduce a candidate new securin, provide an approach for identifying these divergent proteins, reveal a putative anti-fungal therapeutic target, and highlight variations in mitotic regulation in eukaryotes.

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Coordination of Chromatid Separation and Spindle Elongation by Antagonistic Activities of Mitotic and S-Phase CDKs

Cited by 12 publications

References 47 publications

A new linear cyclin docking motif that mediates exclusively S‐phase CDK‐specific signaling

A new linear cyclin docking motif that mediates exclusively S‐phase CDK‐specific signaling

Fin1-PP1 Helps Clear Spindle Assembly Checkpoint Protein Bub1 from Kinetochores in Anaphase

Characterization of a novel separase-interacting protein and candidate new securin, Eip1p, in the fungal pathogen Candida albicans

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