bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2025–07–27
seventeen papers selected by
Valentina Piano, Uniklinik Köln



  1. Sci Rep. 2025 Jul 22. 15(1): 26677
      The spindle assembly checkpoint (SAC) and spindle position checkpoint (SPOC) are essential surveillance systems that ensure accurate chromosome segregation and proper spindle orientation during mitosis. While their individual mechanisms have been extensively studied, their functional integration remains poorly understood. Here, I present a minimal deterministic mathematical model that captures key interactions between SAC and SPOC, incorporating central components such as Mad2, Cdc20, APC/C, Bfa1, Bub2, Tem1, Kin4, and the mitotic kinase Cdc5. The analysis identifies four distinct operational regimes-checkpoint silence, SAC-dominant arrest, SPOC-dominant arrest, and dual-checkpoint arrest-providing a conceptual framework for how cells respond to various spindle defects. This work represents the first comprehensive mathematical framework that integrates these two critical checkpoint systems. The model includes tension-sensitive feedback and demonstrates that deterministic dynamics alone can generate ultrasensitive, switch-like checkpoint responses-without requiring stochastic fluctuations or spatial complexity. Simulations reproduce key experimental observations, including the effects of in vitro mutations in core components and the rheostat-like degradation dynamics of Securin and Cyclin B. Notably, the model exhibits dual regulatory behavior: a bistable toggle switch within the SAC core driven by autocatalytic feedback, and a graded, rheostat-like output at the level of checkpoint satisfaction. This reconciles seemingly contradictory observations of discrete molecular switches with continuous cellular responses. Together, these findings offer a simplified yet predictive framework for dissecting mitotic checkpoint integration and lay the groundwork for future experimental and theoretical studies of SAC-SPOC coordination.
    Keywords:  Ultrasensitive Coordination of SAC–SPOC Checkpoints
    DOI:  https://doi.org/10.1038/s41598-025-11673-9
  2. Cell Rep. 2025 Jul 23. pii: S2211-1247(25)00812-5. [Epub ahead of print]44(8): 116041
      During regulated protein degradation, the 26S proteasome recognizes ubiquitinated substrates through its 19S particle and then degrades them in its 20S enzymatic core. Despite this close interdependency between proteasome subunits, we demonstrate that knockouts from different proteasome subcomplexes result in distinct cellular phenotypes. In particular, depletion of 19S PSMD lid proteins, but not that of other proteasome subunits, prevents bipolar spindle assembly during mitosis. Despite decreased ubiquitin-mediated protein degradation in PSMD knockouts, we find that the monopolar spindle phenotype is instead caused by the aberrant degradation of the kinesin motor protein KIF11. We show that KIF11 degradation occurs through the 20S proteasome in a ubiquitin-independent manner upon loss of 19S proteins and that the resulting alterations in spindle forces lead to the unique monopolar phenotype. Thus, the presence of the 19S particle ensures proper spindle formation by restraining ubiquitin-independent degradation.
    Keywords:  CP: Cell biology; degradation; kinesin; mitosis; proteasome; spindle; ubiquitin
    DOI:  https://doi.org/10.1016/j.celrep.2025.116041
  3. J Cell Biol. 2025 Sep 01. pii: e202301115. [Epub ahead of print]224(9):
      Faithful chromosome segregation requires proper function of the mitotic spindle, which is built from, and depends on, the coordinated regulation of many microtubules and the activities of molecular motors and MAPs. In addition, microtubules themselves are assembled from multiple variants, or isotypes of α- and β-tubulin, yet whether they mediate the activities of motors and MAPs required for proper spindle function remains poorly understood. Here, we use budding yeast to reveal that α-tubulin isotypes regulate opposing outward- and inward-directed forces in the spindle midzone that facilitate optimal spindle elongation and length control. Moreover, we show that the isotypes mediate balanced spindle forces by differentially localizing the antagonistic force generators Cin8 (kinesin-5) and Kar3 (kinesin-14) to interpolar microtubules. Our results reveal new roles for tubulin isotypes in orchestrating motor and MAP activities and provide insights into how forces in the spindle are properly calibrated to ensure proper mitotic spindle morphogenesis.
    DOI:  https://doi.org/10.1083/jcb.202301115
  4. Cell Death Dis. 2025 Jul 18. 16(1): 536
      Recent findings identify a cell-death mechanism in human cancer cells, based on the inhibition of the post-translational modification of NuMA (nuclear mitotic apparatus protein) in cancer cells, which interferes with its protein-binding capacity. NuMA is an indispensable protein for mitosis in both malignant and healthy cells. However, in this cell-death mechanism, only malignant cells are eradicated, due to structural faults inserted in the mitotic spindle poles, causing mitosis arrest. Cell death is imposed in the cancer cells by mitosis arrest, disregarding their mutations.
    DOI:  https://doi.org/10.1038/s41419-025-07868-7
  5. Commun Biol. 2025 Jul 23. 8(1): 1095
      Microtubule-severing enzymes play essential roles in diverse cellular processes, including mitosis and cytokinesis, by modulating microtubule dynamics. In the early branching Trypanosoma brucei, microtubule-severing enzymes are involved in cytokinesis and flagellum length control, but none of them have been found to regulate mitosis. Here we report the characterization of the microtubule-severing enzyme spastin in the procyclic form of T. brucei. We demonstrate that spastin severs microtubule in vitro and overexpression of spastin disrupts spindle microtubules in vivo in trypanosomes, leading to defective chromosome segregation. Knockdown of spastin impairs spindle integrity and disrupts chromosome alignment and segregation. We further show that the function of spastin requires the catalytic AAA-ATPase domain, the microtubule-binding domain, and the microtubule interacting and trafficking domain, and that the association of spastin with spindle depends on the microtubule-binding domain. Together, these results uncover important roles for spastin in chromosome segregation by regulating spindle dynamics in T. brucei.
    DOI:  https://doi.org/10.1038/s42003-025-08505-x
  6. FASEB J. 2025 Jul 31. 39(14): e70854
      KIF16B is a member of the kinesin-3 family of motor proteins, which facilitates processes such as vesicle transport, microtubule dynamics, and organelle function during mitosis. In this study, we explored the role of KIF16B in meiosis. Our findings indicate that KIF16B is involved in the meiotic G2-M transition and spindle assembly in oocytes. KIF16B was consistently expressed throughout the meiotic cell cycle of mouse oocytes. After the occurrence of germinal vesicle breakdown, KIF16B became concentrated on microtubules. The exhaustion of KIF16B induced the impairment of meiotic cell cycle progression, which was due to the inactivation of CDK1 and the reduction in the level of cyclin B1, consequently resulting in the failure of germinal vesicle breakdown. Furthermore, aberrant spindle phenotypes and disordered chromosome alignment were observed in KIF16B-depleted oocytes, along with improper kinetochore-microtubule attachments. These abnormal K-MT attachments resulted in the persistent activation of BubR1/Bub3 at the kinetochores. Moreover, KIF16B knockdown destabilized α-tubulin by affecting the activity of histone deacetylase 6 (HDAC6). Further analysis revealed that KIF16B participated in the Ran GTPase-dependent activation of TPX2, which in turn regulated the phosphorylation levels of Aurora A-polo-like kinase 1 (PLK1), driving the proper assembly of the spindle. In conclusion, our data indicated that KIF16B is crucial for meiosis resumption and spindle assembly in mouse oocytes.
    Keywords:  G2/M transition; kinesin; meiosis; oocyte; spindle
    DOI:  https://doi.org/10.1096/fj.202501664R
  7. Cell Rep. 2025 Jul 23. pii: S2211-1247(25)00790-9. [Epub ahead of print]44(8): 116019
      Ataxia telangiectasia and Rad3-related (ATR) and checkpoint kinase 1 (Chk1) are crucial kinases in the DNA damage response (DDR) pathway. While the roles of ATR and Chk1 within the DDR are well established, their roles in mitosis are not fully understood. Here, we describe that the ATR-Chk1 pathway is rewired during mitosis to promote full CDK1 activity, starkly contrasting its role in interphase, where it inhibits CDK1 following DNA damage in human cells. In mitosis, Chk1 inhibits residual activity of PKMYT1 (Myt1) via direct phosphorylation at Serine 143. Partial loss of CDK1 activity caused by inhibition of mitotic Chk1 leads to different effects on mitotic progression than full CDK1 inhibition. It causes increased lagging chromosomes in part through loss of Aurora B activity. Thus, mitosis-specific ATR-Chk1 activity is necessary to promote faithful chromosome segregation by ensuring that CDK1 activity is maintained in mitosis.
    Keywords:  ATR; CDK1; CP: Molecular biology; Chk1; DNA damage response pathway; cell cycle; chromosome segregation; mitosis
    DOI:  https://doi.org/10.1016/j.celrep.2025.116019
  8. Mol Cells. 2025 Jul 18. pii: S1016-8478(25)00079-2. [Epub ahead of print] 100255
      Protein phosphatase 2A-B56 (PP2A-B56) is a key regulator of mitosis, playing an essential role in maintaining chromosomal stability and ensuring the fidelity of cell division. As a component of the PP2A holoenzyme, the B56 regulatory subunit confers substrate specificity, primarily through interactions with the conserved LxxIxE motif on target proteins. This review highlights the molecular mechanisms by which PP2A-B56 regulates key processes in cell division, including chromosome cohesion and condensation, kinetochore-microtubule attachment, spindle assembly checkpoint (SAC) silencing, and activation of the anaphase-promoting complex/cyclosome (APC/C). In meiosis, PP2A-B56 safeguards centromeric cohesion and facilitates the transition between divisions, with recruitment strategies that differ across species. Recent studies also emphasize its role in protecting oocyte quality and fertility by maintaining chromosomal stability. Furthermore, the competition among multiple LxxIxE-containing substrates for PP2A-B56 binding introduces an additional layer of temporal and spatial regulation. Finally, we discuss how perturbations in PP2A-B56 activity contribute to chromosomal instability and tumorigenesis. Understanding of PP2A-B56's substrate recognition and regulatory dynamics provides a framework for therapeutic targeting in disorders involving defective cell division.
    Keywords:  Chromosome; LxxIxE motif; Meiosis; Mitosis; PP2A-B56; Spindle Assembly Checkpoint
    DOI:  https://doi.org/10.1016/j.mocell.2025.100255
  9. J Mol Cell Biol. 2025 Jul 22. pii: mjaf019. [Epub ahead of print]
      Cells sense and respond to forces from neighbouring cells and the extracellular matrix during growth and division. When cells undergo mitosis in a confined environment like in tumour environment, high compressive stress causes unstable cell cortex and prolonged mitosis. Confined mitotic cells frequently experience chromosome loss and multipolar division. How the cortical instability affects cytokinesis under confinement is unclear. Here, we show that confined mitotic cells undergo furrow ingression comparable to unconfined mitotic cells but are strongly reliant on Aurora B kinase, a catalytic subunit of the chromosomal passenger complex (CPC) for its completion. Mechanistically, the cortical pool of CPC via the scaffolding protein INCENP sustains Aurora B at the equatorial cortex to drive furrow ingression under confinement. We identified mechanoresponsive elements within the single alpha-helix (SAH) domain of INCENP that maintain the cortical CPC at the equatorial cortex to promote furrow ingression in response to high compressive stress. Thus, the cortical INCENP not only binds to actin filaments but also mechanically respond to forces at the equatorial cortex to regulate the CPC during confined cytokinesis.
    Keywords:  confinement; cytokinesis; mechanobiology; mitosis
    DOI:  https://doi.org/10.1093/jmcb/mjaf019
  10. Nat Commun. 2025 Jul 21. 16(1): 6677
      While mitogenic signaling is known to regulate cell-cycle entry during the G1 phase, its function in the G2 phase remains elusive. Here we show that mitogenic signaling controls whether G2-arrested cells proceed through mitosis or undergo whole-genome duplication. Although mitogenic signaling is not required for the G2/M transition under normal conditions, it modulates E2F transcriptional activity via c-Myc. When G2 arrest occurs due to CDK4/6 and CDK2 suppression, E2F activity levels determine the status of APC/C inactivation and the CDK2-Rb feedback loop. Upon release from G2 arrest, cells maintaining APC/C inactivation promptly induce CDK2 activation and FoxM1 phosphorylation, driving mitotic entry. Conversely, APC/C reactivation degrades cyclin A and abolishes the CDK2-Rb loop, necessitating CDK4/6 activation for cell-cycle re-entry. This regulatory mechanism mirrors the G1-phase process, resulting in whole-genome duplication. In cancer cells, this process promotes genome instability and oncogene amplification, contributing to aggressive behavior. These findings reveal a previously unrecognized mitogen-dependent checkpoint that governs cell fate in the G2 phase.
    DOI:  https://doi.org/10.1038/s41467-025-62061-w
  11. Nat Commun. 2025 Jul 22. 16(1): 6736
      Emerging evidence indicates that metabolic signals-including nutrient availability, biosynthetic intermediates, and energy balance-are linked to cell cycle progression. However, how these signals are sensed by the cell cycle machinery remains unclear. Citrate, a key intermediate in the TCA cycle, peaks during mitosis (M phase) and is detected by the glycolytic enzyme ATP-dependent 6-phosphofructokinase 1 muscle isoform (PFKM), accelerating mitotic progression. Mechanistically, citrate binds PFKM, disrupting its tetrameric structure into dimers. Dimeric PFKM interacts with nucleosomes and phosphorylates histone H3 at serine 10 (H3S10), functioning as a protein kinase to promote mitosis and cell proliferation. Structural simulations reveal that PFKM binds nucleosomes optimally when H3S10 aligns with its catalytic site. Disrupting citrate-PFKM or PFKM-H3 interactions reduces H3S10 phosphorylation, delays mitosis, and suppresses tumor growth and T-cell proliferation. Our findings demonstrate that PFKM acts as a citrate sensor, coupling metabolic signals to cell cycle regulation.
    DOI:  https://doi.org/10.1038/s41467-025-62111-3
  12. Cells. 2025 Jul 17. pii: 1094. [Epub ahead of print]14(14):
      Centriole duplication is a vital process for cellular organisation and function, underpinning essential activities such as cell division, microtubule organisation and ciliogenesis. This review summarises the latest research on the mechanisms and regulatory pathways that control this process, focusing on important proteins such as polo-like kinase 4 (PLK4), SCL/TAL1 interrupting locus (STIL) and spindle assembly abnormal protein 6 (SAS-6). This study examines the complex steps involved in semi-conservative duplication, from initiation in the G1-S phase to the maturation of centrioles during the cell cycle. Additionally, we will explore the consequences of dysregulated centriole duplication. Dysregulation of this process can lead to centrosome amplification and subsequent chromosomal instability. These factors are implicated in several cancers and developmental disorders. By integrating recent study findings, this review emphasises the importance of centriole duplication in maintaining cellular homeostasis and its potential as a therapeutic target in disease contexts. The presented findings aim to provide a fundamental understanding that may inform future research directions and clinical interventions related to centriole biology.
    Keywords:  cell cycle control; centriole duplication; chromosomal instability; ciliopathies; oncogenesis
    DOI:  https://doi.org/10.3390/cells14141094
  13. Cancer Sci. 2025 Jul 22.
      Aurora-A (AurA) is a member of the mitotic kinase family and is highly expressed in various tumors. Inhibition of AurA generally leads to fetal mitotic errors. We previously reported that AurA inhibition induces G0/G1 cell cycle arrest in noncancerous cells by promoting the reassembly of primary cilia. However, the mechanisms by which AurA regulates cell cycle progression beyond mitosis remain largely unknown. In this study, we generated noncancerous RPE1 and cancerous HCT116 cell lines expressing endogenous AurA tagged with a minimal auxin-inducible degron (mAID) using CRISPR/Cas9-based gene editing. This system enabled specific and rapid depletion of endogenous AurA protein. By combining this approach with cell synchronization in RPE1 cells, we investigated AurA function specifically in the transition from quiescence to the proliferative cell cycle. Targeted degradation of AurA not only delayed cell cycle progression but also impaired the disassembly of primary cilia at the G0/G1 transition in RPE1 cells. Since this delay in cell cycle progression was rescued by forced deciliation via the knockout of IFT20, AurA facilitates deciliation, which in turn accelerates the transition from quiescence to the proliferative phase of the cell cycle in RPE1 cells. AurA depletion for 4 days increased apoptotic markers in HCT116 cells but not in RPE1 cells. Notably, forced deciliation in RPE1 cells partially enhanced apoptosis induced by AurA depletion. These results suggest that the ability to assemble primary cilia may serve as a protective mechanism against cell death following AurA inhibition.
    Keywords:  Aurora‐A (AurA); auxin‐inducible degron (AID); cell‐cycle reentry; primary cilia; quiescence
    DOI:  https://doi.org/10.1111/cas.70153
  14. Elife. 2025 Jul 23. pii: RP92748. [Epub ahead of print]13
      The cerebral cortex, which is responsible for higher cognitive functions, relies on the coordinated asymmetric division cycles of polarized radial glial progenitor cells for proper development. Defects in the mitotic process of neuronal stem cells have been linked to the underlying causes of microcephaly; however, the exact mechanisms involved are not fully understood. In this study, we present a new discovery regarding the role of the membrane-deforming cytoskeletal regulator protein called Mtss2 (also known as MTSS1L/ABBA) in cortical development. When Mtss2 was absent in the developing brain, it led to a halt in radial glial cell proliferation, disorganized radial fibers, and abnormal migration of neuronal progenitors. During cell division, Mtss2 localized to the cleavage furrow, where it recruited the scaffolding protein Nedd9 and positively influenced the activity of RhoA, a crucial regulator of cell division. Notably, we identified a variant of Mtss2 (R671W) in a patient with microcephaly and intellectual disability, further highlighting its significance. The introduction of this mutant Mtss2 protein in mice resulted in phenotypic similarities to the effects of Mtss2 knockdown. Overall, these findings offer valuable mechanistic insights into the development of microcephaly and the cerebral cortex by identifying Mtss2 as a novel regulator involved in ensuring the accurate progression of mitosis in neuronal progenitor cells.
    Keywords:  ABBA (MTSS1L/MTSS2); RhoA signaling; corticogenesis; human; microcephaly; mitosis; mouse; neuroscience; radial glial cells
    DOI:  https://doi.org/10.7554/eLife.92748
  15. Mol Cell. 2025 Jul 17. pii: S1097-2765(25)00547-7. [Epub ahead of print]85(14): 2796-2811.e5
      Chromatin plays a pivotal role in genome expression, maintenance, and replication. To better understand chromatin organization, we developed a proximity-tagging method to map molecules that associate in 3D space. Using this method-PCP (proximity copy paste)-we mapped the positioning and connectivity of individual nucleosomes in Saccharomyces cerevisiae. We show that chromatin is predominantly organized into regularly spaced nucleosome arrays that can be positioned or delocalized. PCP can also map long-range, multi-way interactions, and we provide direct evidence supporting a model that metaphase chromosomes are compacted by cohesin loop clustering. Analyzing single-molecule nuclease footprinting data, we define distinct chromatin states within a mixed population to show that non-canonical overlapping di-nucleosomes are a stable feature of chromatin. PCP is a versatile method, allowing the detection of the connectivity of individual molecules locally and over large distances to be mapped at high resolution in a single experiment.
    Keywords:  OLDN; PCP; cohesin; nucleosome arrays; overlapping Di-nucleosome; single-molecule
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.018
  16. EMBO J. 2025 Jul 21.
      Complex morphogenetic processes such as cell division require a tight coordination of the activities of microtubules and actin filaments. There is evidence that anillin, conventionally known as an actin-binding and -bundling protein, regulates microtubule/actin crosstalk during cell division. However, it is unknown whether anillin binds directly to microtubules and whether it is sufficient to establish crosslinking between microtubules and actin filaments. Here we address both questions by developing an in vitro system for observing anillin-mediated interactions with actin filaments and dynamic microtubules via total internal-reflection fluorescence microscopy. We find that anillin can interact directly with microtubules and promote microtubule bundling. We confirm that anillin binds and bundles actin filaments, and find that it has a strong preference for actin bundles over individual filaments. Moreover, we show that anillin can directly crosslink microtubules and actin filaments, cause sliding of actin filaments on the microtubule lattice, and transport actin filaments by the growing microtubule tip. Our findings indicate that anillin can potentially serve as a direct regulator of microtubule/actin crosstalk, e.g., during cell division.
    Keywords:  Cell Division; Cytoskeleton; Dynamic Instability; Reconstituted System
    DOI:  https://doi.org/10.1038/s44318-025-00492-3