bims-micesi 2025-11-23 papers

bims-micesi

Biomed News

on Mitotic cell signalling

Issue of 2025–11–23
nine papers selected by
Valentina Piano, Uniklinik Köln

Carboxylate polystyrene nanoplastics disrupt mitotic progression and induce chromosomal instability.
Capturing aberrant cell behaviors producing defects in human embryos via live imaging.
Mechanical coordination between anaphase A and B drives asymmetric chromosome segregation.
A Constitutive Model Deciphers the Viscoelastic Mechanics of Metaphase Spindle Positioning.
Identification and Preliminary Characterization of a Novel Tasquinimod Analog that Unexpectedly Induces Mitotic Arrest by Alteration of Microtubule Dynamics.
Nuclear enlargement induced by overexpression of nuclear export signal is associated with abnormal nuclear division in Schizosaccharomyces pombe.
The telomeric valine-arginine dipeptide repeat protein changes state to diffuse staining in mitosis and represses in vitro translation.
Small-scale siRNA screen reveals WWC2 as a novel regulator of cardiomyocyte mitosis.
MIAT-DHX9 spatiotemporal expression drives venous neointimal hyperplasia through nucleolar homeostasis and mitotic progression.

Ecotoxicol Environ Saf. 2025 Nov 15. pii: S0147-6513(25)01752-X. [Epub ahead of print]307 119407

Carboxylate polystyrene nanoplastics disrupt mitotic progression and induce chromosomal instability.

Jaejung Park, Juyoung Son, Jaehoon Kim, Byung Seok Cha, Wansun Kim, Junyang Jung, Tae Young Yune, Sung Soo Kim, Samjin Choi, Dokyoung Kim, Ja-Eun Kim.

  The widespread use of plastics has raised serious concerns regarding environmental pollution and human health. Although exposure to nanoplastics induces significant toxicities, the mechanisms underlying their genotoxicity, particularly chromosomal instability, remain poorly understood. In this study, we used a non-lethal dose of carboxylate polystyrene nanoplastics (cPS-NPs), which have high reactivity with biological molecules due to enhanced surface reactivity. cPS-NPs accumulated near the centrosomes, inducing supernumerary centrioles accompanied by reduced Aurora kinase A activity. These abnormal centrosomes nucleate excessively stable and hyperpolymerized microtubules, resulting in erroneous kinetochore-microtubule attachments with merotelic and syntelic configurations. Cells treated with cPS-NPs failed to correct these attachment errors, likely due to compromised spindle assembly checkpoints and/or impaired tension sensing, as indicated by the reduced recruitment of Mad2 and BuR1 and low activity of Aurora kinase B and Polo-like kinase 1 to the kinetochores. Consequently, the cells underwent prolonged metaphase, during which excessive pulling forces from the hyperstabilized microtubules triggered premature sister chromatid separation. Persistent misattachments result in misaligned and lagging chromosomes, which can lead to the formation of micronuclei, a widely used marker of genotoxicity. Our findings indicated that a non-lethal dose of cPS-NPs can disrupt mitotic progression. Furthermore, we propose that abnormalities in the centrosomes, microtubules, and chromosomes could serve as potential markers for assessing genotoxicity following acute exposure to a non-lethal dose of nanoplastics.

Keywords:  Carboxylate polystyrene; Chromosomal instability; Micronucleus; Mitosis; Nanoplastics

DOI:  https://doi.org/10.1016/j.ecoenv.2025.119407
Sci Adv. 2025 Nov 21. 11(47): eady6402

Capturing aberrant cell behaviors producing defects in human embryos via live imaging.

Hiroki Akizawa, Ana Domingo-Muelas, Maria Pardo-Figuerez, Blake Hernandez, Goli Ardestani, Robin M Skory, Marta Venturas, Piotr Tetlak, Stephanie Bissiere, Denny Sakkas, Carlos Simon, Nicolas Plachta.

The generation of human embryos in vitro has revolutionized reproductive medicine, and also made it possible to study fundamental aspects of early human development. However, human preimplantation embryos often display an array of morphological defects associated with poor development and implantation. Here, we used live-embryo imaging and computational analysis to capture how these defects can be produced in real time. We record various forms of mitotic errors including lagging chromosomes producing micronuclei, multipolar spindles causing abnormal chromosome organization recapitulated by daughter cells, and uncontrolled scattering of condensed chromosomes. In addition, we capture abnormal cleavage furrow dynamics during cytokinesis producing binucleated and enucleated cells. Finally, we find cells with disrupted mitotic progression ultimately leading to blebbing and fragmentation. Thus, these results document specific aberrant cell behaviors producing morphological defects in real time, and indicate that errors during mitosis and cytokinesis represent a major cause of developmental failures in human embryos.

DOI: https://doi.org/10.1126/sciadv.ady6402
bioRxiv. 2025 Oct 04. pii: 2025.10.02.680008. [Epub ahead of print]

Mechanical coordination between anaphase A and B drives asymmetric chromosome segregation.

Ana M Dias Maia Henriques, Tim Davies, Serge Dmitrieff, Nicolas Minc, Julie C Canman, Julien Dumont, Gilliane Maton.

Chromosome segregation during anaphase occurs through two mechanistically distinct processes: anaphase A, in which chromosomes move toward spindle poles, and anaphase B, in which the anaphase spindle elongates through cortical astral microtubule pulling forces. Caenorhabditis elegans embryos have been thought to rely primarily on anaphase B, with little to no contribution from anaphase A. Here, we uncover a novel anaphase A mechanism in C. elegans embryos, driven by the kinesin-13 KLP-7 MCAK and opposed by the kinesin-12 KLP-18. We found that the extent of chromosome segregation during anaphase A is asymmetrically regulated by cell polarity cues and modulated by mechanical tension within the spindle, generated by opposing forces acting on chromosomes and spindle poles. Additionally, we found that the contribution of anaphase A to chromosome segregation increases progressively across early embryonic divisions. These findings uncover an unexpected role for anaphase A in early C. elegans development and reveal a KLP-7 MCAK -dependent mechanical coordination between anaphase A and anaphase B driven chromosome segregation.
eTOC summary: Dias Maia Henriques et al. uncover an anaphase A pathway, driven by the kinesin-13 KLP-7 and opposed by the kinesin-12 KLP-18, that contributes to chromosome segregation in early C. elegans embryos. Its activity is regulated by spindle tension, cell polarity cues, and progressively increases during early embryonic divisions.

DOI: https://doi.org/10.1101/2025.10.02.680008
Biophys J. 2025 Nov 14. pii: S0006-3495(25)00751-9. [Epub ahead of print]

A Constitutive Model Deciphers the Viscoelastic Mechanics of Metaphase Spindle Positioning.

Houbo Sun, Yuehua Yang, Hongyuan Jiang.

The precise positioning and orientation of mitotic spindles are critical for ensuring accurate segregation of daughter cells during tissue development. Spindle positioning machinery-composed of astral microtubules and motor proteins-must withstand diverse mechanical forces, requiring robust mechanical properties. However, due to the difficulty in experimental measurements, the viscoelastic properties of this machinery remain poorly understood. Here, we develop a three-dimensional model to systematically investigate the dynamic mechanical responses of spindle positioning machinery. Our simulations reveal that this machinery exhibits distinct viscoelastic behavior in response to stepwise force and displacement loadings. Building upon these observations, we propose a minimal constitutive model comprising three parallel branches: (1) cytoplasmic drag (purely viscous branch), (2) microtubule elasticity (spring branch), and (3) motor-mediated stress dissipation (a Maxwell branch, i.e., spring-dashpot in series). Through parametric analysis, we demonstrate that increased microtubule rescue/growth rates enhance spindle positioning stability by strengthening microtubule-mediated elastic restoration-specifically through an increase in the spring branch's elastic coefficient. Conversely, elevated dynein motor trunover destabilizes positioning via two synergistic mechanisms: reducing effective stiffness (decreased spring coefficient) and accelerating motor-driven stress relaxation (shortened Maxwell relaxation time). Overall, the proposed constitutive model has the potential to replace complex simulations and provide more insightful predictions, thus advancing our understanding of spindle positioning mechanisms.

DOI: https://doi.org/10.1016/j.bpj.2025.11.016
ACS Med Chem Lett. 2025 Nov 13. 16(11): 2336-2345

Identification and Preliminary Characterization of a Novel Tasquinimod Analog that Unexpectedly Induces Mitotic Arrest by Alteration of Microtubule Dynamics.

Ghassan M Abushaikha, Dewmi Rathnayake, Abdel Bayazid, Shreyas Wadwekar, Negin Abdollahi, Safiyyah Hasan, Kierra Nickelson, Isaac Kaba, Tyler J Chitwood, William R Taylor.

  While investigating the SAR associated with tasquinimod, whose anticancer activity is primarily derived from inhibition of S100A9 and HDAC4, we designed and prepared several analogues. We identified a potent hit (FB2) that showed cytotoxicity against several cancer cells with IC50s between 0.3 and 2.0 μM. Surprisingly, FB2 appeared to halt cells during mitosis. To better define the relevance of FB2's unanticipated action, we further explored its mechanism and found that it significantly alters microtubule dynamics. KT-1 exposed to FB2 showed an elongated cellular morphology with condensed chromosomes and mitotic spindles. FB2 also reduced the rate of microtubule regrowth in cells; however, we are unable to conclude whether this is due to direct binding to tubulin or to some indirect mechanism involving initial interaction with some other target sites. These effects on tubulin dynamics are likely responsible for defects in spindle structure, mitotic arrest, and the observed robust killing of cancer cells.

Keywords:  HCT-116; Hela cells; Mitotic arrest; Tasquinimod; Taxol

DOI:  https://doi.org/10.1021/acsmedchemlett.5c00521
Biol Open. 2025 Nov 18. pii: bio.062331. [Epub ahead of print]

Nuclear enlargement induced by overexpression of nuclear export signal is associated with abnormal nuclear division in Schizosaccharomyces pombe.

Takahiro Fujimoto, Suzu Watanabe, Yuko Imamura, Masaki Mizunuma, Kazunori Kume.

  The size of the nucleus is tightly coordinated with cell size across eukaryotes, yet the physiological significance of maintaining proper nuclear dimensions remains poorly understood. Here, we investigate how nuclear size dysregulation resulting from perturbed nucleocytoplasmic transport affects mitotic fidelity in Schizosaccharomyces pombe. Overexpression of a GFP-tagged nuclear export signal (NES-GFP) induces nuclear expansion, leading to severe growth defects and frequent errors in chromosome segregation during mitosis. Live-cell imaging revealed that enlarged nuclei underwent delayed mitotic progression and abnormal nuclear division. Strikingly, genetic suppression of nuclear expansion alleviated these defects, whereas enhancement of nuclear size exacerbated them. Together, these findings suggest that maintaining proper nuclear dimensions contributes to accurate chromosome segregation, although additional effects of NES-GFP overproduction and other factors influencing nuclear size should be further examined.

Keywords:  Closed mitosis; Fission yeast; Nuclear size; Nucleocytoplasmic transport

DOI:  https://doi.org/10.1242/bio.062331
Proc Natl Acad Sci U S A. 2025 Nov 25. 122(47): e2520441122

The telomeric valine-arginine dipeptide repeat protein changes state to diffuse staining in mitosis and represses in vitro translation.

Taghreed Al-Turki, Venkata Mantri, Smaranda Willcox, C Allie Mills, Laura E Herring, Su-Ji Cho, Hannah Lee, Caliyn Meyer, E S Anton, Jack D Griffith.

  Translation of mammalian G-rich telomeric RNA via the Repeat Associated non-AUG (AUG, the mRNA start codon) mechanism can produce proteins consisting of long repeats of valine-arginine (VR) or glycine-leucine (GL) dipeptides. Their role in the cell has not been elucidated. Using confocal laser scanning microscopy combined with antibody staining we previously observed VR sequestered in punctate bodies and liquid droplets in the cytoplasm and nuclei of nonmitotic cells. Here, we report that cells in mitosis show diffuse VR staining throughout the cell, giving these cells a bright appearance. Upon mitotic enrichment using the cyclin-dependent kinase 1 (CDK1) inhibitor RO-3306. RO-3306, 100% of the mitotic cells showed the same diffuse staining. Antibody staining showed colocalization of VR and the L4 ribosomal protein in mitotic cells and in an in vitro firefly luciferase assay, VR depressed translation. Affinity purification combined with mass spectrometry identified ribosomal proteins as the major class of VR interacting proteins in U2OS cells including L4 along with tubulin and proteins related to neural degenerative diseases. This change from a sequestered, punctate state in interphase to dispersed diffuse staining in mitosis, and the affinity of VR for the L4 protein which lines the ribosomal exit tunnel suggests that an oligomerization change of VR may facilitate its involvement in inhibiting of global translation during mitosis. Extension to mouse embryonic cerebral cortical development showed clear staining in the ventricular zone where neural progenitor cells with a high mitotic index proliferate and in the cortical plate where new neurons settle.

Keywords:  dipeptide repeat proteins; mitosis; ribosomes; telomere

DOI:  https://doi.org/10.1073/pnas.2520441122
J Mol Cell Cardiol. 2025 Nov 15. pii: S0022-2828(25)00204-4. [Epub ahead of print]210 127-136

Small-scale siRNA screen reveals WWC2 as a novel regulator of cardiomyocyte mitosis.

Dogacan Yücel, Calvin Smith, Natalia Ferreira de Araujo, Fernando Souza-Neto, Upendra Chalise, Grace Schuler, Bayardo I Garay, Jennifer L Mikkila, Omar Atef Abdelhamid Mahmoud, Pratima Mandal, Rita C R Perlingeiro, Jop H van Berlo.

  (145): Adult cardiomyocytes exit the cell cycle soon after birth, although this shift can be reversed by molecular interventions. To identify novel regulators of cardiomyocyte proliferation, we performed a comparative transcriptomic analysis of actively proliferating and non-proliferating cardiomyocytes across key pre-and post-natal developmental timepoints. Integration of bioinformatics analyses with a functional screen of 238 differentially expressed genes identified WWC2 as a regulator of cell cycle exit. Inhibition of Wwc2 induced cell cycle entry with completion of mitosis and cytokinesis, while overexpression of WWC2 induced cell cycle exit. Moreover, inhibition of Wwc2 resulted in dedifferentiation of cardiomyocytes with reduced expression of sarcomeric and calcium handling genes. Mechanistically, WWC2 binds to 14-3-3 and regulates YAP phosphorylation and expression. In vivo, deletion of Wwc2 stimulated cardiac regeneration after myocardial infarction. These results identify WWC2 as an important regulator of cardiomyocyte cell cycle exit and initiation of the maturation process.

Keywords:  Cardiomyocyte; Cell cycle; Cytokinesis; Maturation; Proliferation

DOI:  https://doi.org/10.1016/j.yjmcc.2025.11.004
Cell Rep. 2025 Nov 18. pii: S2211-1247(25)01350-6. [Epub ahead of print]44(12): 116578

MIAT-DHX9 spatiotemporal expression drives venous neointimal hyperplasia through nucleolar homeostasis and mitotic progression.

Yue Lou, Wen-Hao Tian, Jia-Long Cui, Guo-Zhu Sun, Fan Lv, Xian-Hui Liang, Kai Huang, Qing-Ping Yao, Ying-Xin Qi.

  Venous neointimal hyperplasia, characterized by abnormal smooth muscle cell (SMC) proliferation, represents a critical contributor to stenosis and therapeutic failure following vascular interventions. Here, we identified spatiotemporal nucleolar expression of DExH-box helicase 9 (DHX9) and its binding partner, long non-coding RNA (lncRNA) myocardial infarction-associated transcript (MIAT), using multi-super-resolution imaging and single-molecule fluorescence in situ hybridization (FISH). In normal SMCs, DHX9 transiently localized to nucleoli during the early S phase. CRISPR-mediated MIAT activation facilitated DHX9's nucleolar localization and interaction with PARP1. MIAT also drove SMC proliferation by accelerating cell cycle progression. Depleting MIAT or DHX9 led to nucleolar disorganization, mitotic defects, and DNA damage. Using deep learning, we identified nucleolar-associated morphological features as potential biomarkers for cellular status and disease progression. In an ex vivo and animal model, knockdown of MIAT-DHX9 suppressed SMC proliferation and intimal hyperplasia. Our findings establish the MIAT-DHX9 axis as a central regulator of SMC nucleolar homeostasis and mitotic progression, offering a nucleolus-centered strategy to suppress neointimal hyperplasia.

Keywords:  CP: molecular biology; DHX9; cell cycle; lncRNA MIAT; mitosis; nucleolus; vascular diseases

DOI:  https://doi.org/10.1016/j.celrep.2025.116578