bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2025–04–13
nine papers selected by
Valentina Piano, Uniklinik Köln
  1. The spindle assembly checkpoint: Molecular mechanisms and kinase-targeted drug discovery.
  2. Proximity-based activation of AURORA A by MPS1 potentiates error correction.
  3. Plasticity of mitotic cyclins in promoting the G2-M transition.
  4. Supra-second tracking and live-cell karyotyping reveal principles of mitotic chromosome dynamics.
  5. Rules of engagement for condensins and cohesins guide mitotic chromosome formation.
  6. The chromosomal challenge of human embryos: Mechanisms and fundamentals.
  7. α-Fodrin-CENP-E interaction is critical for pancreatic cancer progression and drug response.
  8. Prolonged metaphase II arrest weakens Aurora B/C-dependent error correction in mouse oocytes.
  9. Targeting Eg5 using Arry520 combats gastric cancer by inducing monopolar spindles.
  1. Drug Discov Today. 2025 Apr 09. pii: S1359-6446(25)00068-6. [Epub ahead of print] 104355
    The spindle assembly checkpoint: Molecular mechanisms and kinase-targeted drug discovery.
    Inês Lima, Fernanda Borges, António Pombinho, Daniel Chavarria.
      The spindle assembly checkpoint (SAC) is a surveillance mechanism required for the fidelity of chromosome segregation, ensuring that anaphase is not initiated until all chromosomes are properly attached to the mitotic spindle. In cancer cells, SAC inactivation leads to aneuploidy beyond the cell's adaptation, culminating in cell death. This review provides a concise overview of the SAC signaling process and properties. Recent drug discovery strategies to selectively target kinases, particularly Aurora B and monopolar spindle kinase (MPS1), aimed at developing innovative anticancer agents able to override SAC are also presented.
    Keywords:  cancer; chromosomal instability; drug discovery; mitosis; spindle assembly checkpoint
    DOI:  https://doi.org/10.1016/j.drudis.2025.104355
  2. Curr Biol. 2025 Apr 03. pii: S0960-9822(25)00303-3. [Epub ahead of print]
    Proximity-based activation of AURORA A by MPS1 potentiates error correction.
    Nelson Leça, Francisca Barbosa, Sergi Rodriguez-Calado, Arianna Esposito Verza, Margarida Moura, Paulo D Pedroso, Inês Pinto, Elena Artes, Tanja Bange, Claudio E Sunkel, Marin Barisic, Thomas J Maresca, Carlos Conde.
      Faithful cell division relies on mitotic chromosomes becoming bioriented with each pair of sister kinetochores bound to microtubules oriented toward opposing spindle poles. Erroneous kinetochore-microtubule attachments often form during early mitosis but are destabilized through the phosphorylation of outer kinetochore proteins by centromeric AURORA B kinase (ABK) and centrosomal AURORA A kinase (AAK), thus allowing for re-establishment of attachments until biorientation is achieved.1,2,3,4,5,6,7,8,9 MPS1-mediated phosphorylation of NDC80 has also been shown to directly weaken the kinetochore-microtubule interface in yeast.10 In human cells, MPS1 has been proposed to transiently accumulate at end-on attached kinetochores11 and phosphorylate SKA3 to promote microtubule release.12 Whether MPS1 directly targets NDC80 and/or promotes the activity of AURORA kinases in metazoans remains unclear. Here, we report a novel mechanism involving communication between kinetochores and centrosomes, wherein MPS1 acts upstream of AAK to promote error correction. MPS1 on pole-proximal kinetochores phosphorylates the C-lobe of AAK, thereby increasing its activation at centrosomes. This proximity-based activation ensures the establishment of a robust AAK activity gradient that locally destabilizes mal-oriented kinetochores near spindle poles. Accordingly, MPS1 depletion from Drosophila cells causes severe chromosome misalignment and erroneous kinetochore-microtubule attachments, which can be rescued by tethering either MPS1 or constitutively active AAK mutants to centrosomes. Proximity-based activation of AAK by MPS1 also occurs in human cells to promote AAK-mediated phosphorylation of the NDC80 N-terminal tail. These findings uncover an MPS1-AAK crosstalk that is required for efficient error correction, showcasing the ability of kinetochores to modulate centrosome outputs to ensure proper chromosome segregation.
    Keywords:  AURORA A; MPS1; cell division; centrosome; error correction; kinetochore; mitosis
    DOI:  https://doi.org/10.1016/j.cub.2025.03.018
  3. J Cell Biol. 2025 Jun 02. pii: e202409219. [Epub ahead of print]224(6):
    Plasticity of mitotic cyclins in promoting the G2-M transition.
    Adrijana Crncec, Ho Wai Lau, Lau Yan Ng, Hoi Tang Ma, Joyce P Y Mak, Hon Fung Choi, Tsz Kwan Yeung, Randy Yat Choi Poon.
      Cyclins and cyclin-dependent kinases (CDKs) orchestrate key events in the cell cycle. However, the uniqueness of individual mitotic cyclins has been a long-standing puzzle. By rapidly removing cyclins in G2 human cells, we found that deficiency of B-type cyclins attenuates mitotic onset and uncouples the G2-M kinase network from mitosis, resulting in sustained activation of PLK1 and cyclin A-CDK1. This culminates in mitotic slippage without completing nuclear envelope breakdown. Remarkably, elevating cyclin A several-fold above its endogenous level is adequate to restore mitosis, allowing cells to survive without B-type cyclins. In contrast, cyclin A is rate-limiting but not essential for G2-M due to compensation by endogenous cyclin B1-CDK2, a non-canonical pair. These findings challenge the traditional indispensable roles of different cyclins and highlight their plasticity. Due to the high malleability of the A- and B-type cyclins, cancer cells may be able to place different weights on different cyclins, while maintaining sufficient CDK activities for successful mitosis.
    DOI:  https://doi.org/10.1083/jcb.202409219
  4. Nat Cell Biol. 2025 Apr;27(4): 654-667
    Supra-second tracking and live-cell karyotyping reveal principles of mitotic chromosome dynamics.
    Rumen Stamatov, Sonya Uzunova, Yoana Kicheva, Maria Karaboeva, Tavian Blagoev, Stoyno Stoynov.
      Mitotic chromosome dynamics are essential for the three-dimensional organization of the genome during the cell cycle, but the spatiotemporal characteristics of this process remain unclear due to methodological challenges. While Hi-C methods capture interchromosomal contacts, they lack single-cell temporal dynamics, whereas microscopy struggles with bleaching and phototoxicity. Here, to overcome these limitations, we introduce Facilitated Segmentation and Tracking of Chromosomes in Mitosis Pipeline (FAST CHIMP), pairing time-lapse super-resolution microscopy with deep learning. FAST CHIMP tracked all human chromosomes with 8-s resolution from prophase to telophase, identified 15 out of 23 homologue pairs in single cells and compared chromosomal positioning between mother and daughter cells. It revealed a centrosome-motion-dependent flow that governs the mapping between chromosome locations at prophase and their metaphase plate position. In addition, FAST CHIMP measured supra-second dynamics of intra- and interchromosomal contacts. This tool adds a dynamic dimension to the study of chromatin behaviour in live cells, promising advances beyond the scope of existing methods.
    DOI:  https://doi.org/10.1038/s41556-025-01637-6
  5. Science. 2025 Apr 11. 388(6743): eadq1709
    Rules of engagement for condensins and cohesins guide mitotic chromosome formation.
    Kumiko Samejima, Johan H Gibcus, Sameer Abraham, Fernanda Cisneros-Soberanis, Itaru Samejima, Alison J Beckett, Nina Puǎčeková, Maria Alba Abad, Christos Spanos, Bethan Medina-Pritchard, James R Paulson, Linfeng Xie, A Arockia Jeyaprakash, Ian A Prior, Leonid A Mirny, Job Dekker, Anton Goloborodko, William C Earnshaw.
      We used Hi-C, imaging, proteomics, and polymer modeling to define rules of engagement for SMC (structural maintenance of chromosomes) complexes as cells refold interphase chromatin into rod-shaped mitotic chromosomes. First, condensin disassembles interphase chromatin loop organization by evicting or displacing extrusive cohesin. Second, condensin bypasses cohesive cohesins, thereby maintaining sister chromatid cohesion as sisters separate. Studies of mitotic chromosomes formed by cohesin, condensin II, and condensin I alone or in combination lead to refined models of mitotic chromosome conformation. In these models, loops are consecutive and not overlapping, implying that condensins stall upon encountering each other. The dynamics of Hi-C interactions and chromosome morphology reveal that during prophase, loops are extruded in vivo at ∼1 to 3 kilobases per second by condensins as they form a disordered discontinuous helical scaffold within individual chromatids.
    DOI:  https://doi.org/10.1126/science.adq1709
  6. HGG Adv. 2025 Apr 09. pii: S2666-2477(25)00040-5. [Epub ahead of print] 100437
    The chromosomal challenge of human embryos: Mechanisms and fundamentals.
    Anna Ivanova, Elena Korchivaia, Maria Semenova, Igor Lebedev, Ilya Mazunin, Ilya Volodyaev.
      Chromosomal abnormalities in human preimplantation embryos, originating from either meiotic or mitotic errors, present a significant challenge in reproductive biology. Complete aneuploidy is primarily linked to errors during the resumption of meiosis in oocyte maturation, which increase with maternal age, while mosaic aneuploidies result from mitotic errors after fertilization. The biological causes of these abnormalities are increasingly becoming a topic of interest for research groups and clinical specialists. This review explores the intricate processes of meiotic and early mitotic divisions in embryos, shedding light on the mechanisms that lead to changes in chromosome number in daughter cells. Key factors in meiotic division include difficulties in spindle assembly without centrosomes, kinetochore orientation disturbances, and inefficient cell cycle checkpoints. The weakening of cohesion molecules that bind chromosomes, exacerbated by maternal aging, further complicates chromosomal segregation. Mitotic errors in early development are influenced by defects in sperm centrosomes, kinetochore misalignment, and the gradual depletion of maternal regulatory factors. Coupled with the inactive or partially active embryonic genome, this depletion increases the likelihood of chromosomal aberrations. While various theoretical mechanisms for these abnormalities exist, current data remain insufficient to determine their exact contributions. Continued research is essential to unravel these complex processes and improve outcomes in assisted reproductive technologies.
    Keywords:  Chromosomal mosaicism; aneuploidy; cell cycle checkpoints; chromosome segregation errors; kinetochore orientation; meiotic errors; mitotic errors
    DOI:  https://doi.org/10.1016/j.xhgg.2025.100437
  7. Cell Cycle. 2025 Apr 10. 1-25
    α-Fodrin-CENP-E interaction is critical for pancreatic cancer progression and drug response.
    Athira Jyothy, Julfequar Hussain, Sharanya C S, Vineetha Radhakrishnan Chandraprabha, Madhumathy G Nair, Smreti Vasudevan, Hariharan Sreedharan, Betty Abraham, Tessy Thomas Maliekal, Kathiresan Natarajan, Suparna Sengupta.
      α-Fodrin, a known scaffolding protein for cytoskeleton stabilization, performs various functions including cell adhesion, cell motility, DNA repair and apoptosis. Based on our previous results revealing its role in mitosis in glioblastoma, we have examined its effect in pancreatic cancer, which is often linked to mitotic aberrations including aneuploidy and chromosome instability. Here, we show that the expression of α-Fodrin increases in pancreatic adenocarcinoma tissues compared to its normal counterpart, suggesting its tumor promoting role. shRNA-mediated knock-down of α-Fodrin significantly reduces the xenograft growth in immunocompromised mice underscoring the importance of α-Fodrin in tumor progression. CENP-E (centromere-associated protein E) is a motor protein essential for chromosomal alignment and segregation during mitosis. We have found that α-Fodrin interacts with CENP-E to recruit it to the kinetochore and depletion of α-Fodrin has a crucial role in controlling aneuploidy. As these mitotic defects can lead to apoptosis, we have further evaluated the activation of possible upstream pathways. Paclitaxel, a chemotherapeutic agent that stabilizes microtubules, disrupts mitosis and induces apoptosis. We found that Paclitaxel triggered stronger activation of JNK, ERK, and P38 MAPKs, altered BCL2/BAX ratios, cytochrome C release causing increased apoptosis in α-Fodrin knockdown cells compared to cells with wild-type α-Fodrin. This enhanced sensitivity to paclitaxel is consistent with improved survival in pancreatic cancer patients with low α-Fodrin (SPTAN1) and low CENP-E expression compared to poor prognosis with high expressions of both the genes. Taken together, this study provides the molecular mechanism by which α-Fodrin - CENP-E axis regulates pancreatic cancer progression and drug response.
    Keywords:  CENP-E; apoptosis; drug sensitivity; mitotic defects; pancreatic cancer; α-Fodrin
    DOI:  https://doi.org/10.1080/15384101.2025.2485837
  8. Curr Biol. 2025 Apr 04. pii: S0960-9822(25)00315-X. [Epub ahead of print]
    Prolonged metaphase II arrest weakens Aurora B/C-dependent error correction in mouse oocytes.
    Antoine Langeoire, Alison Kem-Seng, Damien Cladière, Katja Wassmann, Eulalie Buffin.
      Chromosome segregation during meiosis is highly error-prone in mammalian oocytes. The mechanisms controlling chromosome attachments and the spindle assembly checkpoint (SAC) have been extensively studied in meiosis I, but our knowledge of these mechanisms during meiosis II is rather limited. Although mammalian oocytes arrest in metaphase II for an extended period awaiting fertilization, some misattached chromosomes may persist. This suggests that the mechanism correcting misattachments is not fully functional during the arrest. In this study, we investigated whether low inter-kinetochore tension, which characterizes incorrect attachments, can be detected by Aurora B/C-dependent error correction in meiosis II. We found that low tension, induced by low dose of STLC in early metaphase II, does indeed mediate microtubule detachment by Aurora B/C and, consequently, anaphase II delay through SAC activation. Surprisingly, we also found that, during prolonged metaphase II arrest, Aurora B/C activity is no longer sufficient to detach low-tension attachments, correlating with high accumulation of PP2A at kinetochores. As a result, the SAC is not activated, and sister chromatids segregate in anaphase II without delay even in the presence of low tension. Hence, during the prolonged metaphase II arrest to await fertilization, oocytes become unable to discriminate between correct and incorrect attachments and may allow errors to persist.
    Keywords:  Aurora B/C; SAC; error correction; meiosis; oocyte; spindle; tension
    DOI:  https://doi.org/10.1016/j.cub.2025.03.030
  9. Gene. 2025 Apr 03. pii: S0378-1119(25)00246-X. [Epub ahead of print]955 149458
    Targeting Eg5 using Arry520 combats gastric cancer by inducing monopolar spindles.
    Na He, Xinyuan Wei, Ruofei Sun, Gengyuan Zhang, Jie Zhao, Xiangyan Jiang, Bo Long, Zeyuan Yu, Wengui Shi, Zuoyi Jiao.
      Eg5, also known as KIF11, is a motor protein essential for establishing a bipolar spindle and ensuring proper chromosome congression during mitosis. It is amplified in various human cancers and serves as a critical oncogene driving tumour progression. However, the role and clinical significance of Eg5 in gastric cancer has remained elusive. In this study, we showed that Eg5 is upregulation in gastric cancer tissues and is negatively associated with patient prognosis. The ablation of Eg5 inhibits the proliferation and migration of gastric cancer cells and suppresses tumour growth in xenograft mice. Mechanistically, Eg5 ablation induces the formation of monopolar spindle, leading to cell apoptosis and consequent inhibition of tumour growth. Furthermore, Arry520 is demonstrated as a potent Eg5 inhibitor which blocks tumour growth by increasing the formation of cell monopolar spindle and inducing apoptosis. Arry520 exhibits efficiently therapeutic effects on gastric cancer in tumour organoid models, cell-derived xenografts and patient-derived xenografts (PDX) in mice. Collectively, our findings provide evidence for the oncogenic properties of the mitotic protein Eg5 and identify Arry520 as a promising strategy to combat gastric cancer.
    Keywords:  Eg5; Eg5 inhibitor; Gastric cancer; Mitotic kinesin protein
    DOI:  https://doi.org/10.1016/j.gene.2025.149458
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