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Kinetochore protein Cnn1 promotes sister chromatid bi-orientation by modulating intraKMN affinities in a biphasic, phospho-regulated manner.

ABSTRACT: Kinetochores are large proteinaceous structures that assemble on centromeres to align sister chromatids to the mitotic spindle and orchestrate their segregation to the daughter cells. At the core of kinetochores lies a network of proteins known as KMN, whose microtubule-binding activity is regulated by the Ipl1/Aurora B and Mps1 kinases. Here, we have characterized a novel structural yeast kinetochore protein named Cnn1 and show that it regulates KMN-spindle activity by modulating the affinity between the KMN subcomplexes at their basis. Cnn1 supports KMN from S phase to anaphase, and is controlled by the Cdc28, Mps1 and Ipl1 kinases. Cnn1 has evolved to associate the KMN complexes into a coherent network activity to ensure efficient

ORGANISM(S): Saccharomyces cerevisiae

PROVIDER: GSE31567 | GEO | 2012/05/06

SECONDARY ACCESSION(S): PRJNA145699

REPOSITORIES: GEO

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A common molecular mechanism underlies the role of Mps1 in chromosome biorientation and the spindle assembly checkpoint

Project description:The conserved Mps1 kinase corrects improper kinetochore-microtubule attachments, thereby ensuring chromosome biorientation. Yet, its critical targets in this process remain elusive. Mps1 is also involved in the spindle assembly checkpoint (SAC), the surveillance mechanism halting chromosome segregation until biorientation is attained. Its role in SAC activation is antagonized by the PP1 phosphatase and involves phosphorylation of Knl1/Spc105, which recruits Bub1 to kinetochores to promote assembly of SAC effector complexes. A crucial question is whether error correction and SAC activation are part of a single device or separable pathways. Here we characterise a novel yeast mutant, mps1-3, defective in chromosome biorientation and SAC activation. Through an unbiased screen for suppressors, we found that mutations lowering PP1 levels at Spc105 or forced association of Bub1 with Spc105 reinstate both chromosome biorientation and SAC signalling in mps1-3 cells. Our data strongly argue that Mps1-dependent phosphorylation of the Knl1/Spc105 kinetochore scaffold is critical for Mps1 function in both chromosome biorientation and SAC activation, thus supporting the idea that a common sensory apparatus simultaneously elicits error correction and SAC signalling.

2020-02-05 | GSE144741 | GEO

Mps1 regulates kinetochore-microtubule attachment stability via the Ska complex to ensure error-free chromosome segregation

Project description:Spindle assembly checkpoint (SAC) regulators such as the Mps1 kinase not only delay anaphase onset, but also correct improper chromosome-spindle linkages that would otherwise lead to missegregation and aneuploidy. However, the substrates and mechanisms involved in this pathway of error correction remain poorly understood. Using a chemically tuned kinetochore-targeting assay, we show that Mps1 destabilizes microtubule attachments (K-fibers) epistatically to Aurora B, the other major error-correcting kinase. Through chemical genetics and quantitative proteomics, we identify both known and novel sites of Mps1- regulated phosphorylation at the outer kinetochore. Modification of these substrates was sensitive to microtubule tension and counterbalanced by the PP2A-B56 phosphatase, a positive regulator of chromosome-spindle interactions. Consistently, Mps1 inhibition rescued K-fiber stability after depleting PP2A-B56. We also identify the hinge region of the W-shaped Ska complex as a key effector of Mps1 at the kinetochore-microtubule interface, as mutations that mimic constitutive phosphorylation strongly destabilized K-fibers in vivo and inhibited the Ska complex’s conversion from lattice diffusion to end-coupled microtubule binding in vitro. Together these results provide new insights into how Mps1 modulates the microtubule-binding properties of the kinetochore to promote the selective stabilization of bipolar attachments and error-free chromosome segregation.

2018-10-24 | PXD006135 | Pride

Pcs1 and Mde4 are inner centromere proteins required to prevent merotelic kinetochore orientation

Project description:Chromosome segregation depends on proper attachment of sister kinetochores to microtubules. Merotelic kinetochore orientation is an error which occurs when a single kinetochore is attached to microtubules emanating form opposite poles. Mechanisms preventing or correcting the merotelic attachment must operate to avoid chromosome missegregation. Pcs1 has been implicated in preventing merotelic attachment in mitosis and meiosis II. We describe here the identification of Mde4 protein which forms a complex with the Pcs1. Both Mde4 and Pcs1 localize to the central core of the centromere. Similarly to the pcs1 mutant, in the absence of mde4 lagging chromosomes are frequently observed during mitosis and meiosis II . We provide the first evidence that the lagging chromosomes in pcs1 and mde4 mutants are due to merotelic kinetochore orientation. Keywords: ChIP-chip analysis ChIP-chip analysis: In all cases, hybridization data for ChIP fraction was compared with that of SUP (supernatant) fraction. Pombe whole chromosome array was used.

2010-06-10 | E-GEOD-5257 | biostudies-arrayexpress

Pcs1 and Mde4 are inner centromere proteins required to prevent merotelic kinetochore orientation

2007-06-18 | GSE5257 | GEO

Greatwall kinase regulates SAC by controlling phosphorylation and activity of MPS1

Project description:The Greatwall/Mastl kinase is an essential gene, which regulates the phosphatase activity that counteracts the phosphorylation of Cdk1 substrates. Although Mastl-/- MEFs can enter mitosis, they are unable to complete mitosis due to chromosome segregation defects. Here, we show that Mastl is essential for robust spindle assembly checkpoint (SAC) maintenance. Mastl-/- MEFs display reduced phosphorylation and kinase activity of MPS1, which causes mislocalization of MPS1, Mad1, and Aurora B from the kinetochore and the inner centromere regions. This results in premature inactivation of SAC signalling and early anaphase onset without correction of chromosome-spindle attachment mistakes. Treatment of the knockout cells with protein phosphatase II inhibitor okadaic acid (OA) rescued decreased MPS1 activity, mislocalization of Aurora B, Mad1, MPS1, and premature mitotic slippage. Our data demonstrates how regulation of PP2A activity by Mastl kinase prevents premature SAC silencing as a result of controlling the phosphorylation status and activity of MPS1.

2018-10-26 | PXD004882 | Pride

Bub1 and CENP-U redundantly recruit Plk1 to stabilize kinetochore-microtubule attachments and ensure accurate chromosome segregation

Project description:Bub1 is required for the kinetochore/centromere localization of two essential mitotic kinases Plk1 and Aurora B. Surprisingly, stable depletion of Bub1 by ~95% in human cells marginally affects whole chromosome segregation fidelity. We show that CENP-U, which is recruited to kinetochores by the CENP-P and CENP-Q subunits of the CENP-O complex, is required to prevent chromosome mis-segregation in Bub1-depleted cells. Mechanistically, Bub1 and CENP-U redundantly recruit Plk1 to kinetochores to stabilize kinetochore-microtubule attachments, thereby ensuring accurate chromosome segregation. Furthermore, unlike its budding yeast homolog, the CENP-O complex does not regulate centromeric localization of Aurora B. Consistently, depletion of Bub1 or CENP-U sensitizes cells to the inhibition of Plk1 but not Aurora B kinase activity. Taken together, our findings provide mechanistic insight into the regulation of kinetochore function, which may have implications for targeted treatment of cancer cells with mutations perturbing kinetochore recruitment of Plk1 by Bub1 or the CENP-O complex.

2021-08-29 | GSE182827 | GEO

Genetic enhancers of partial PLK1 inhibition reveal hypersensitivity to kinetochore perturbations

Project description:Polo-like kinase 1 (PLK1) is a serine/threonine kinase required for mitosis and cytokinesis. As cancer cells are often hypersensitive to partial PLK1 inactivation, chemical inhibitors of PLK1 have been developed and tested in clinical trials. However, these molecules alone were not completely effective. PLK1 promotes numerous molecular and cellular events in the cell division cycle. To date, it is unclear which of these events most crucially depend on PLK1 activity. We used a CRISPR-based genome-wide screening strategy to identify genes whose inactivation enhances cell proliferation defects upon partial chemical inhibition of PLK1. Genes identified encode proteins that are functionally linked to PLK1 in multiple ways. Among them, factors that promote centromere and kinetochore function were clearly enriched. In particular, inactivation of the kinesin KIF18A or SKA1 in PLK1-compromised cells results in mitotic defects, activation of the spindle assembly checkpoint and nuclear reassembly defects. Our results suggest that functions of PLK1 at kinetochores are most sensitive to its inhibition, and point at KIF18A as a possible target for combinatorial therapies using existing PLK1 inhibitors.

2023-10-02 | GSE228155 | GEO

Discovery of kinetochore and spindle assembly checkpoint proteins in apicomplexan parasites

Project description:Kinetochores are multiprotein assemblies that bind chromosomes to the spindle during mitosis. Despite conserved roles, repertoires of kinetochore proteins vary greatly across eukaryotes. In particular, most known components are not clearly detected in a group of parasites known as the Apicomplexa. Furthermore, flexibility in scale of amplification and an apparent incapability to delay cell cycle progression in response to spindle integrity has coined an idea these parasites divide in the absence of spindle checkpoints. In this study, we reunite divergent apicomplexan kinetochore components to a common eukaryotic set and additionally identify 9 kinetochore proteins that share little homology to known proteins. AKiTs are essential for chromosome segregation and show modes of division parallel to eukaryotic metaphase to anaphase transition and spindle assembly checkpoint signaling. These findings suggest conserved spindle assembly checkpoint signaling maintains fidelity during chromosome segregation in apicomplexan parasites.

2023-03-11 | PXD028595 | Pride

Monopolar attachment of sister kinetochores at meiosis I requires casein kinase 1.

Project description:The segregation of maternal centromeres away from the paternal ones during the first division of meiosis depends on the attachment of sister kinetochores to microtubules emanating from the same spindle pole. In budding yeast monopolar attachment requires the recruitment to kinetochores of a protein complex called monopolin. The biochemical function of monopolin was unknown. Here, we have identified the casein kinase I Hrr25 as a hitherto unknown subunit of monopolin. Hrr25 differs from other monopolin components by its enzymatic activity and strong evolutionary conservation. We demonstrate that Hrr25’s kinase activity and its interaction with monopolin are both required for monopolar attachment. Accordingly, Hrr25 is associated with centromeres in meiosis I. Our results revealed a surprising new role for casein kinases and provide a hypothesis for the mechanism of monopolar attachment during meiosis I in sexually reproducing organisms: casein kinase I-dependent phosphorylation of kinetochore proteins. Keywords: ChIP-chip, Meiosis, Cell cycle, Saccharomyces cerevisiae, Chromosome VI tiling array, Hrr25, Mam1

2006-09-23 | GSE4792 | GEO

RNA-seq analysis of Control and Mps1sKO testis at P10

Project description:Monopolar spindle 1 (Mps1), which plays a critical role in somatic mitosis, has also been revealed to be essential for meiosis I in oocytes. Spermatogenesis is an important process involving successive mitosis and meiosis, but the function of Mps1 in spermatogenesis remains unclear. Here, we generated Mps1 conditional knockout mice and found that Ddx4-cre-driven loss of Mps1 in male mice resulted in depletion of undifferentiated spermatogonial cells and subsequently of differentiated spermatogonia and spermatocytes. In addition, Stra8-cre-driven ablation of Mps1 in male mice led to germ cell loss and fertility reduction. Spermatocytes lacking Mps1 were blocked at the zygotene-to-pachytene transition in prophase of meiosis I, and the expression of many meiotic genes was decreased, while that of apoptotic genes was increased. Moreover, we also detected increased apoptosis in spermatocytes with Mps1 knockout, which may have been the reason why germ cells were lost. Taken together, our findings indicate that Mps1 is required for mitosis of gonocytes and spermatogonia, differentiation of undifferentiated spermatogonia, and progression of meiosis I in spermatocytes.

2021-05-24 | GSE165143 | GEO

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