bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2025–09–14
ten papers selected by
Valentina Piano, Uniklinik Köln
  1. The BUB1 and BUBR1 paralogs scaffold the kinetochore fibrous corona.
  2. Aurora A regulates the material property of spindle poles to orchestrate nuclear organization at mitotic exit.
  3. DNA damage in mitosis: SOD1 delays anaphase onset.
  4. Cdk1-dependent lamin aggregation underlies oxidative stress-induced nuclear shape abnormalities.
  5. Aurora B inhibition induces polyploidy and mitotic catastrophe in HER2-amplified breast cancer: Telomere shortening as a potential anticancer mechanism of AZD1152-HQPA.
  6. CDK1-mediated phosphorylation of LDHA fuels mitosis through LDHB-dependent lactate oxidation.
  7. Titin Is Present in the Elastic Tethers That Connect Separating Anaphase Chromosomes in Crane-Fly Spermatocytes.
  8. Hbo1 and Msl complexes preserve differential compaction and H3K27me3 marking of active and inactive X chromosomes during mitosis.
  9. CUDC-907 exerts an inhibitory effect on non-small cell lung cancer associated with induction of mitotic catastrophe and downregulation of YAP/TAZ signaling.
  10. Evodiamine induces centrosome amplification with subsequent G2/M cell cycle arrest in primary vascular smooth muscle cells.
  1. Sci Adv. 2025 Sep 12. 11(37): eady6890
    The BUB1 and BUBR1 paralogs scaffold the kinetochore fibrous corona.
    Verena Cmentowski, Andrea Musacchio.
      The kinetochore corona, a polymeric fibrous structure, facilitates chromosome biorientation and mitotic checkpoint signaling during mitosis. How its main building block, the ROD-Zwilch-ZW10 (RZZ) complex, assembles on the outer kinetochore remains poorly understood. Harnessing corona biochemical reconstitutions and cell biology, we reveal that the paralogous spindle assembly checkpoint (SAC) proteins BUB1 and BUBR1 promote nonredundant branches of corona assembly. MPS1 kinase-dependent kinetochore docking of BUB1 and subsequent recruitment of BUBR1 initiates assembly. Disrupting the first branch by depleting CENP-E, a kinesin that links BUBR1 to RZZ, uncovered a second assembly pathway mediated by a direct interaction between BUB1 and ROD. Discovery of a direct interaction with the RZZ explains how the SAC protein MAD1 fits this corona assembly scheme. Our findings solve the long-standing puzzle of corona assembly and demonstrate the intimate interweaving of chromosome biorientation and checkpoint signaling.
    DOI:  https://doi.org/10.1126/sciadv.ady6890
  2. EMBO J. 2025 Sep 12.
    Aurora A regulates the material property of spindle poles to orchestrate nuclear organization at mitotic exit.
    Ashwathi Rajeevan, Vignesh Olakkal, Madhumitha Balakrishnan, Dwaipayan Chakrabarty, François Charon, Daan Noordermeer, Sachin Kotak.
      Animal cells dismantle their nuclear envelope (NE) at the beginning and reconstruct it at the end of mitosis. This process is closely coordinated with spindle pole organization: poles enlarge at mitotic onset and reduce in size as mitosis concludes. The significance of this coordination remains unknown. Here, we demonstrate that Aurora A maintains a pole-localized protein NuMA in a dynamic state during anaphase. Without Aurora A activity, NuMA shifts from a dynamic to a solid state and abnormally accumulates at the poles, causing the segregated chromosome sets to bend around the NuMA-enriched poles. NuMA localization at the poles relies on interactions with dynein/dynactin, its coiled-coil domain, and an intrinsically disordered region (IDR). Mutagenesis experiments revealed that cation-π interactions within IDR are key for NuMA pole localization, while glutamine residues trigger the solid-state transition of NuMA upon Aurora A inhibition. We propose that maintaining the proper material properties of the spindle poles is a key step in choreographing the accurate organization of the nucleus and genome post-mitosis.
    Keywords:  Aurora A; Material Property; NuMA; Nuclear Shape; Spindle Poles
    DOI:  https://doi.org/10.1038/s44318-025-00564-4
  3. FEBS J. 2025 Sep 12.
    DNA damage in mitosis: SOD1 delays anaphase onset.
    George Zachos.
      Unrepaired DNA double strand breaks (DSBs) can lead to genomic instability, carcinogenesis, or cell death; however, mitotic cells do not exhibit a DNA damage checkpoint delay and do not repair DSBs until the next cell cycle. Instead, DSBs can delay anaphase through the mitotic spindle checkpoint by an incompletely understood mechanism. Li et al. now show that, in human mitotic cells with damaged DNA, superoxide dismutase 1 inhibits protein phosphatase 2a, which dephosphorylates kinetochore proteins to silence the spindle checkpoint, leading to persistent spindle checkpoint activation and delayed anaphase onset. Here, the biological significance of these findings and open questions are discussed.
    Keywords:  DNA damage; PP2a; SOD1; anaphase; kinetochores; mitosis; phosphatase
    DOI:  https://doi.org/10.1111/febs.70264
  4. BMB Rep. 2025 Sep 08. pii: 6369. [Epub ahead of print]
    Cdk1-dependent lamin aggregation underlies oxidative stress-induced nuclear shape abnormalities.
    Ju-Hyun Ahn, Min-Guk Cho, Abdul Basit, In-Kang Song, Kong-Joo Lee, Jae-Ho Lee.
      Altered nuclear morphology, one of the characteristics of cancer cells, is often indicative of tumor prognosis. While reactive oxygen species (ROS) are known to induce nuclear morphology changes, mechanisms underlying these effects remain elusive, particularly regarding nuclear assembly. We hypothesized that mitotic cells might exhibit increased susceptibility to ROSinduced nuclear deformation due to the dynamic nature of nuclear envelope during mitosis, i.e., disassembly and reassembly. Interestingly, we discovered that exposure of mitotic cells to hydrogen peroxide (H2O2) resulted in persistence of lamin aggregates during early mitosis, which coincided with aberrant nuclear morphology. Further investigation revealed a dampening effect of H2O2 on Cdk1, a pivotal kinase governing mitotic entry. Our in vitro kinase assays demonstrated that H2O2 mediated reduction of Cdk1 activity, resulting in diminished phosphorylation of lamin, a key Cdk1 substrate. Notably, restoration of Cdk1 activity rescued lamin phosphorylation, thereby mitigating lamin aggregation. Furthermore, persistence of lamin aggregation during mitotic entry correlated with premature reassembly of lamin during mitotic exit, affecting nuclear envelope reassembly. These findings collectively suggest that ROS-mediated perturbation of Cdk1 activity during early mitosis can trigger lamin aggregation that affects lamin reassembly, thereby disrupting nuclear morphology. Our study elucidates a novel mechanism by which ROS can disrupt nuclear architecture by modulating Cdk1 activity during mitosis.
  5. Biomed Pharmacother. 2025 Sep 08. pii: S0753-3322(25)00703-6. [Epub ahead of print]191 118509
    Aurora B inhibition induces polyploidy and mitotic catastrophe in HER2-amplified breast cancer: Telomere shortening as a potential anticancer mechanism of AZD1152-HQPA.
    Somayeh Alsadat Tara, Ali Zekri, Fattah Sotoodehnejadnematalahi, Mohammad Hossein Modarressi.
      Polyploidy, a conserved mechanism involved in normal development and tissue homeostasis, plays a paradoxical role in cancer by facilitating both tumor progression and therapeutic vulnerability. Although polyploidization may confer survival advantages to cancer cells, its controlled induction could represent an effective anticancer strategy. Aurora B kinase, a critical regulator of mitosis, plays a pivotal role in ensuring chromosomal integrity and preventing polyploidy. However, its role in chromosome ploidy and telomere length maintenance in breast cancer remains insufficiently explored. In this study, we identified a significant association between Aurora B overexpression and poor prognosis exclusively in patients with HER2-amplified breast cancer. Treatment with AZD1152-HQPA, a selective Aurora B kinase inhibitor, significantly reduced cell viability and colony-forming potential, with a pronounced effect on HER2-amplified breast cancer cell lines. Importantly, we found that Aurora B inhibition is sufficient to induce polyploidy/multinucleation (8 N and 16 N), cellular enlargement, and mitotic catastrophe. Furthermore, we observed telomere shortening, downregulation of the human telomerase reverse transcriptase (hTERT) and TERRA (telomeric repeat-containing RNA), and a concomitant increase in ROS production following Aurora B inhibition and polyploidization. Mechanistically, we investigated the protein-protein interaction between Aurora B kinase and upstream regulators of hTERT. Collectively, this study elucidates a novel anticancer mechanism associated with Aurora B inhibition, revealing that AZD1152-HQPA not only impairs mitotic fidelity and promotes polyploidization but also compromises the telomere/telomerase maintenance system. These findings highlight the therapeutic potential of Aurora B inhibitors in targeting telomere-associated vulnerabilities in polyploid cancer cells.
    Keywords:  AZD1152-HQPA; Aurora B kinase; Cancer cell vulnerability; HER2-amplified breast cancer; Polyploidy; Telomere shortening; hTERT
    DOI:  https://doi.org/10.1016/j.biopha.2025.118509
  6. EMBO Rep. 2025 Sep 12.
    CDK1-mediated phosphorylation of LDHA fuels mitosis through LDHB-dependent lactate oxidation.
    Mengting Liu, Aoxing Cheng, Weiyi You, Jiaxin Wu, Chenxu Dai, Ting Wang, Ying Wu, Fumei Zhong, Jue Shi, Yingying Du, Zhonghuai Hou, Ping Gao, Ke Ruan, Yi Yang, Yuzheng Zhao, Kaiguang Zhang, Zhenye Yang, Jing Guo.
      While cancer cells overexpress lactate dehydrogenase A (LDHA) to support glycolytic flux and lactate production, the role of LDHB-which preferentially catalyzes lactate oxidation-remains unclear. Here, we demonstrate that LDHB, but not LDHA, is essential for mitotic progression in cancers. During mitosis, CDK1 phosphorylates LDHA at threonine 18, reducing its incorporation into the lactate dehydrogenase (LDH) tetramer. This results in LDHB-enriched tetramers that shift catalytic activity toward lactate oxidation, converting lactate and NAD⁺ into pyruvate and NADH. The generated NADH fuels oxidative phosphorylation and ATP production, thereby sustaining mitosis. Notably, LDHA-T18 phosphorylation occurs exclusively in tumor tissues. Our findings reveal a tumor-specific mechanism in which CDK1 reprograms LDH isoenzyme composition to direct lactate toward NADH production, ensuring energy homeostasis during mitosis. This underscores the therapeutic necessity of targeting both LDHA and LDHB in cancer.
    Keywords:  ATP; Lactate; Lactate Dehydrogenase; Mitosis; NADH
    DOI:  https://doi.org/10.1038/s44319-025-00573-8
  7. Cytoskeleton (Hoboken). 2025 Sep 09.
    Titin Is Present in the Elastic Tethers That Connect Separating Anaphase Chromosomes in Crane-Fly Spermatocytes.
    Demetra Economopoulos, Maral Janan, Martina Krüger, Aavo-Valdur Mikelsaar, Arthur Forer, Rose Sheykhani.
      Elastic tethers connect telomeres of separating chromosomes in anaphase of animal cells. Immunofluorescence staining of titin in crane-fly spermatocytes, using 4 different antibodies, shows that the giant elastic protein titin seems to be a component of mitotic tethers: titin "strands" extend between separating chromosomes, connecting their telomeres, just as tethers do. Since titin is responsible for elastic forces in myofibrils, we suggest that titin is responsible for the backwards forces exerted on chromosome arms during anaphase.
    Keywords:  chromosomes; connectin (titin); fluorescent antibody technique; meiosis; mitotic tethers; myofibrilsanaphase
    DOI:  https://doi.org/10.1002/cm.70035
  8. Nat Cell Biol. 2025 Sep;27(9): 1482-1495
    Hbo1 and Msl complexes preserve differential compaction and H3K27me3 marking of active and inactive X chromosomes during mitosis.
    Dounia Djeghloul, Sherry Cheriyamkunnel, Bhavik Patel, Holger Kramer, Alex Montoya, Karen E Brown, Chad Whilding, Tatyana B Nesterova, Guifeng Wei, Neil Brockdorff, Iga Grządzielewska, Remzi Karayol, Asifa Akhtar, Matthias Merkenschlager, Amanda G Fisher.
      In mammals, chromosome-wide regulatory mechanisms ensure a balance of X-linked gene dosage between males (XY) and females (XX). In female cells, expression of genes from one of the two X chromosomes is curtailed, with selective accumulation of Xist-RNA, Xist-associated proteins, specific histone modifications (for example, H3K27me3) and Barr body formation observed throughout interphase. Here we show, using chromosome flow-sorting, that during mitosis, Xist-associated proteins dissociate from inactive X (Xi) chromosomes, while high levels of H3K27me3 and increased compaction of the Xi relative to active X (Xa), are retained. Proteomic comparison of mitotic Xi and Xa revealed that components of Hbo1 and Msl/Mof histone acetyltransferase complexes are significantly enriched on Xa as compared to Xi and autosomes. By contrast, inhibitors of histone acetylation co-enrich with Xi. Furthermore, inhibition of Hbo1 or deletion of Msl/Mof components functionally abolishes mitotic differences in H3K27me3 marking and chromosome compaction. These data uncover critical roles for acetylation pathways in preserving X chromosome properties during mitosis.
    DOI:  https://doi.org/10.1038/s41556-025-01748-0
  9. Chem Biol Interact. 2025 Sep 09. pii: S0009-2797(25)00365-5. [Epub ahead of print] 111735
    CUDC-907 exerts an inhibitory effect on non-small cell lung cancer associated with induction of mitotic catastrophe and downregulation of YAP/TAZ signaling.
    Yuan Liu, Xiao Qi, Xin-Peng Luo, Yi-Fei Wang, Jia-Jun Wan, Feng-Ze Wang, Wei-Ying Zhang.
      Non-small cell lung cancer (NSCLC) is the most common histologic subtype of lung cancer associated with a relatively high mortality rate. CUDC-907, a dual-target inhibitor of histone deacetylase (HDAC) and phosphatidylinositol 3-kinase (PI3K), has the potential to suppress the progression of various malignancies. However, the anti-cancer effect of CUDC-907 on NSCLC remains to be fully elucidated. In this study, we explored the anti-NSCLC effects of CUDC-907 and the possible underlying mechanisms. NSCLC cells were treated with different concentrations of CUDC-907, and cell viability was detected using the Cell Counting Kit-8 (CCK-8) assay. Cell proliferation was evaluated using colony formation and 5-ethynyl-2'-deoxyuridine (EdU) assays, while γ- H2A.X variant histone (H2AX) immunofluorescence was used to monitor DNA damage. The in vivo anti-tumor efficacy of CUDC-907 against NSCLC was evaluated using a xenograft mouse model, and protein expression levels were examined via Western blot analysis. The results revealed that CUDC-907 reduced the viability of A549 and H1299 cells in a concentration-dependent manner. Colony formation and EdU assays showed that CUDC-907 suppressed the proliferation of NSCLC cells. Exposure to CUDC-907 caused G2/M phase arrest in both A549 and H1299 cells by decreasing the expression of cyclin A, cell division cycle 25C (Cdc25C), p-Cdc25C, Cdc2, and cyclin B1, and increasing the protein levels of p21. Treatment with CUDC-907 induced H2AX foci formation and abnormal mitosis in NSCLC cells by downregulating the expression of Aurora A, Aurora B, and polo-like kinase 1 (PLK1). In addition, CUDC-907 triggered A549 and H1299 cell apoptosis by increasing the cleavage of caspase-3, caspase-8, caspase-9, and poly (ADP-ribose) polymerase (PARP). Mechanistic studies revealed that CUDC-907 activated inositol-requiring enzyme 1 α (IRE1α)-c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK) pathway, and blocked yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling in A549 and H1299 cells. Additionally, CUDC-907 treatment significantly inhibited tumor growth and reduced tumor weight in the tumor xenograft mouse model. Taken together, this study revealed the cytotoxic effects of CUDC-907 and its underlying mechanism, which suggests that CUDC-907 may be an effective therapeutic approach for treating NSCLC.
    Keywords:  CUDC-907; DNA damage; Mitotic catastrophe; NSCLC; YAP
    DOI:  https://doi.org/10.1016/j.cbi.2025.111735
  10. Biochem Pharmacol. 2025 Sep 09. pii: S0006-2952(25)00585-4. [Epub ahead of print] 117320
    Evodiamine induces centrosome amplification with subsequent G2/M cell cycle arrest in primary vascular smooth muscle cells.
    Patricia Haiss, Rongxia Liu, Feng Xian, David Gomez Varela, Manuela Schmidt, Verena M Dirsch, Tina Blažević.
      Evodiamine (EVO) is a natural product found in Tetradium ruticarpum. It inhibits vascular smooth m uscle cell (VSMC) proliferation, a key mechanism in the pathogenesis of atherosclerosis and restenosis. This study characterizes the mechanism of action behind the antiproliferative activity of evodiamine in platelet derived growth factor (PDGF)-activated VSMC. We confirmed the antiproliferative activity of EVO (0.3 and 1 µmol/L) in cultured primary VSMC by resazurin conversion and bromo-deoxyuridine (BrdU) incorporation assays, respectively, and its ability to arrest VSMC in G2/M by flow cytometric cell cycle analysis. Annexin V- Fluorescein Isothiocyanate (FITC)/propidium iodide (PI) staining and western blot analysis of caspase-3 cleavage detected low levels of apoptosis in response to 3 µmol/L EVO. We demonstrate that EVO (3 µmol/L) induces mitotic catastrophe (MC), as evidenced by characteristic nuclear morphology observed by confocal microscopy and polyploidy detected by flow cytometric DNA content analysis. Mechanistically, we rule out DNA damage as a cause of MC by western blot analysis of phospho-Ser139 histone H2A.X (γH2A.X). Instead, EVO induces centrosome amplification involving polo-like kinase 4 (PLK4) signaling. This is evident in cells co-treated with EVO (3 µmol/L) and the PLK4 inhibitor centrinone B (CENB) at 125 nmol/L by blunted centrosome amplification and cell cycle arrest. The study concludes with a proteomic analysis of purified centrosomes, which identifies candidates involved in this mechanism. In conclusion, evodiamine induces mitotic catastrophe via centrosome amplification in VSMC, positioning it as an antiproliferative agent with a distinct mechanism.
    Keywords:  Cell cycle; Centrosomes; Evodiamine; Mitotic catastrophe; Vascular smooth muscle cells
    DOI:  https://doi.org/10.1016/j.bcp.2025.117320
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