bims-micesi 2025-05-25 papers

bims-micesi

Biomed News

on Mitotic cell signalling

Issue of 2025–05–25
fifteen papers selected by
Valentina Piano, Uniklinik Köln

Interplay of kinetochores and catalysts drives rapid assembly of the mitotic checkpoint complex.
Rewriting the rules of cell division.
Stu2 is required for plus-end directed chromosome transport along microtubules during metaphase in Saccharomyces cerevisiae.
Actin organizes chromosomes and microtubules to ensure mitotic fidelity in the preimplantation embryo.
Chromosome Segregation in Closed Mitosis Under an Excess of Nuclear Envelope.
A novel SUN1-ALLAN complex coordinates segregation of the bipartite MTOC across the nuclear envelope during rapid closed mitosis in Plasmodium berghei.
Cell competition eliminates aneuploid human pluripotent stem cells.
Mutual regulation between cell cycle and transcription termination factor TTF2.
Structure of the microtubule-anchoring factor NEDD1 bound to the γ-tubulin ring complex.
The neural stem cell gene PAFAH1B1 controls cell cycle progression, DNA integrity, and paclitaxel sensitivity of triple-negative breast cancer cells.
The multifaceted functions of SPC25 in cancer: from molecular pathways to targeted therapy.
The Schizosaccharomyces pombe nucleolar protein Nsk1 modulates rDNA silencing during interphase.
The Overexpression of Collagen Receptor DDR1 is Associated With Chromosome Instability and Aneuploidy in Diffuse Large B-Cell Lymphoma.
Structural regulation of PLK1 activity: implications for cell cycle function and drug discovery.
Centromere Protein F in Tumor Biology: Cancer's Achilles Heel.

Nat Commun. 2025 May 24. 16(1): 4823

Interplay of kinetochores and catalysts drives rapid assembly of the mitotic checkpoint complex.

Suruchi Sethi, Sabrina Ghetti, Verena Cmentowski, Teresa Benedetta Guerriere, Patricia Stege, Valentina Piano, Andrea Musacchio.

The spindle assembly checkpoint (SAC) ensures mitotic exit occurs only after sister chromatid biorientation, but how this coordination is mechanistically achieved remains unclear. Kinetochores, the megadalton complexes linking chromosomes to spindle microtubules, contribute to SAC signaling. However, whether they act solely as docking platforms or actively promote the co-orientation of SAC catalysts such as MAD1:MAD2 and BUB1:BUB3 remains unresolved. Here, we reconstitute kinetochores and SAC signaling in vitro to address this question. We engineer recombinant kinetochore particles that recruit core SAC components and trigger checkpoint signaling upon Rapamycin induction, and test their function using a panel of targeted mutants. At approximately physiological concentrations of SAC proteins, kinetochores are essential for efficient mitotic checkpoint complex (MCC) assembly, the key effector of SAC signaling. Our results suggest that kinetochores serve not only as structural hubs but also as catalytic platforms that concentrate and spatially organize SAC components to accelerate MCC formation and ensure timely checkpoint activation.

DOI: https://doi.org/10.1038/s41467-025-59970-1
Science. 2025 May 22. 388(6749): 817-818

Rewriting the rules of cell division.

William Bement.

Microtubules get help from actin filaments during mitosis.

DOI: https://doi.org/10.1126/science.ady2201
MicroPubl Biol. 2025 ;2025

Stu2 is required for plus-end directed chromosome transport along microtubules during metaphase in Saccharomyces cerevisiae.

Julia R Torvi, Jonathan Wong, David G Drubin, Georjana Barnes.

Chromosome alignment on the mitotic spindle, also referred to as congression, is facilitated by translocation of side-bound chromosomes along the microtubule surface, which allows the establishment of end-on attachment of kinetochores to microtubule plus ends. We use a reconstitution assay in lysates prepared from metaphase-arrested budding yeast to show that kinetochore translocation along the lateral surface of microtubules is dependent on Stu2, a homolog of vertebrate XMAP215. Stu2 tracks both growing and shrinking microtubule ends but also colocalizes with moving lattice-bound kinetochores. In cells, we observed that Stu2 depletion impairs chromosome biorientation during metaphase.

DOI: https://doi.org/10.17912/micropub.biology.001577
Science. 2025 May 22. 388(6749): eads1234

Actin organizes chromosomes and microtubules to ensure mitotic fidelity in the preimplantation embryo.

Blake Hernandez, Piotr Tetlak, Ana Domingo-Muelas, Hiroki Akizawa, Robin M Skory, Goli Ardestani, Mate Biro, Xiaolei Liu, Stephanie Bissiere, Denny Sakkas, Nicolas Plachta.

Following fertilization, the preimplantation embryo undergoes successive rounds of cell division and must accurately propagate the genetic material to ensure successful development. However, early mammalian embryos lack efficient spindle assembly mechanisms, and it remains unclear how error-free chromosome segregation is achieved. In this work, we imaged early mouse embryos and identified a network of nuclear actin cables that organize prophase chromosomes at the nuclear periphery. Following nuclear envelope breakdown, the network contracts and gathers chromosomes toward the cell center. Network contraction was driven by filament disassembly in a myosin II-independent manner. Additionally, we identified a network of branched actin filaments that attenuates metaphase spindle elongation. We also visualized nuclear actin in human embryos, suggesting a conserved role for actin in ensuring mitotic fidelity during early mammalian development.

DOI: https://doi.org/10.1126/science.ads1234
Biol Cell. 2025 May;117(5): e70011

Chromosome Segregation in Closed Mitosis Under an Excess of Nuclear Envelope.

Noelia Rodríguez-Herrera, Silvia Santana-Sosa, Sara Medina-Suárez, Samantha Morais-Armas, Emiliano Matos-Perdomo, Félix Machín.

   BACKGROUND: Two major types of cell division occur in eukaryotic cells regarding the dismantlement or not of the nuclear envelope (NE) in mitosis, open and closed mitosis, respectively. In the budding yeast Saccharomyces cerevisiae, the prototypical model for closed mitosis, the Nem1-Spo7 phosphatase complex, which regulates lipid metabolism, plays a key role in coordinating NE expansion throughout the cell cycle. Indeed, Nem1 depletion leads to abnormal NE evaginations in interphase, which protrude the ribosomal DNA (rDNA) and the nucleolus. However, the specific impact of these NE and chromosome organization abnormalities during chromosome segregation in anaphase remains poorly understood.
RESULTS: Our study investigated chromosome segregation and NE dynamics during closed mitosis in relation to the presence or absence of Nem1. Nem1 was depleted by means of the auxin degron system. Nem1 depletion led to the formation of chromatin protrusions in interphase, particularly at the rDNA locus, as it has been reported before for nem1 mutants. These protrusions persisted into anaphase and were associated with delayed recoiling of the rDNA-bearing chromosome XII right arm, resulting in lagging chromatin during late anaphase. Additionally, cells can maintain nucleus-vacuole junctions (NVJs) during anaphase, suggesting that vacuoles may play a role in shaping NE morphology during chromosome segregation.
CONCLUSION: Our findings suggest that the Nem1-Spo7/lipin regulation of the NE size is crucial for the timely segregation of the rDNA-bearing chromosome during closed mitosis. Thus, the NE homeostasis actively contributes to chromosome segregation and the spatial organization of chromosomes in subsequent cell cycles. In addition, the persistent association between the NE and vacuoles in anaphase further underscores how cumbersome organelle interactions can become during closed mitosis, opening inspiring research avenues.

Keywords:  Lipin; Nem1; Nvj1; Saccharomyces cerevisiae; chromosome segregation; closed mitosis; nuclear envelope; rDNA; vacuole

DOI:  https://doi.org/10.1111/boc.70011
Elife. 2025 May 20. pii: RP106537. [Epub ahead of print]14

A novel SUN1-ALLAN complex coordinates segregation of the bipartite MTOC across the nuclear envelope during rapid closed mitosis in Plasmodium berghei.

Mohammad Zeeshan, Igor Blatov, Ryuji Yanase, David J P Ferguson, Sarah L Pashley, Zeinab Chahine, Yoshiki Yamaryo-Botté, Akancha Mishra, Baptiste Marche, Suhani Bhanvadia, Molly Hair, Sagar Batra, Robert Markus, Declan Brady, Andrew R Bottrill, Sue Vaughan, Cyrille Y Botté, Karine G Le Roch, Anthony A Holder, Eelco Tromer, Rita Tewari.

  Mitosis in eukaryotes involves reorganisation of the nuclear envelope (NE) and microtubule-organising centres (MTOCs). During male gametogenesis in Plasmodium, the causative agent of malaria, mitosis is exceptionally rapid and highly divergent. Within 8 min, the haploid male gametocyte genome undergoes three replication cycles (1N to 8N), while maintaining an intact NE. Axonemes assemble in the cytoplasm and connect to a bipartite MTOC-containing nuclear pole (NP) and cytoplasmic basal body, producing eight flagellated gametes. The mechanisms coordinating NE remodelling, MTOC dynamics, and flagellum assembly remain poorly understood. We identify the SUN1-ALLAN complex as a novel mediator of NE remodelling and bipartite MTOC coordination during Plasmodium berghei male gametogenesis. SUN1, a conserved NE protein, localises to dynamic loops and focal points at the nucleoplasmic face of the spindle poles. ALLAN, a divergent allantoicase, has a location like that of SUN1, and these proteins form a unique complex, detected by live-cell imaging, ultrastructural expansion microscopy, and interactomics. Deletion of either SUN1 or ALLAN genes disrupts nuclear MTOC organisation, leading to basal body mis-segregation, defective spindle assembly, and impaired spindle microtubule-kinetochore attachment, but axoneme formation remains intact. Ultrastructural analysis revealed nuclear and cytoplasmic MTOC miscoordination, producing aberrant flagellated gametes lacking nuclear material. These defects block development in the mosquito and parasite transmission, highlighting the essential functions of this complex.

Keywords:  P. berghei; basal body; cell biology; gametogenesis; infectious disease; malaria; microbiology; nuclear enevelope; transmission

DOI:  https://doi.org/10.7554/eLife.106537
Stem Cell Reports. 2025 May 08. pii: S2213-6711(25)00110-9. [Epub ahead of print] 102506

Cell competition eliminates aneuploid human pluripotent stem cells.

Amanda Ya, Chenhui Deng, Kristina M Godek.

  Human pluripotent stem cells (hPSCs) maintain diploid populations for generations despite frequent mitotic errors that cause aneuploidy or chromosome imbalances. Consequently, aneuploid hPSC propagation must be prevented to sustain genome stability, but how this is achieved is unknown. Surprisingly, we find that, unlike somatic cells, uniformly aneuploid hPSC populations with heterogeneous abnormal karyotypes proliferate. Instead, in mosaic populations, cell-non-autonomous competition between neighboring diploid and aneuploid hPSCs eliminates less fit aneuploid cells, regardless of specific chromosome imbalances. Aneuploid hPSCs with lower MYC or higher p53 levels relative to diploid neighbors are outcompeted but conversely gain an advantage when MYC and p53 relative abundance switches. Thus, MYC- and p53-driven cell competition preserves hPSC genome integrity despite their low mitotic fidelity and intrinsic capacity to proliferate with an aneuploid genome. These findings have important implications for using hPSCs in regenerative medicine and for how diploid human embryos form during development despite the prevalence of aneuploidy.

Keywords:  MYC; aneuploidy; cell competition; human pluripotent stem cells; mosaicism; p53; preimplantation embryos

DOI:  https://doi.org/10.1016/j.stemcr.2025.102506
Sci China Life Sci. 2025 May 22.

Mutual regulation between cell cycle and transcription termination factor TTF2.

Yuying Hu, Lele Xu, Bicong Feng, Qingnan Wu, Yan Wang, Wei Gong, Mengzhu Lv, Huihui Zhao, Jie Chen, Jinting Li, Weimin Zhang, Qimin Zhan.

  Most transcriptional activities are silent during mitosis and reactivated upon mitotic exit; however, the underlying detailed mechanisms are still largely unknown. We revealed that the cell cycle regulatory machinery anaphase-promoting complex/cyclosome (APC/C) and mitotic checkpoint complex (MCC) are coupled with transcription termination to modulate cell cycle progression via the transcription termination factor TTF2. The protein level of TTF2 oscillated during cell cycle progression, and increased in the S and G2/M phases while maintaining a low level in late mitosis and the G1 phase. Knockdown of TTF2 induced G2/M arrest, while overexpression of TTF2 accelerated the M/G1 transition and promoted cell proliferation. Mechanistic studies revealed that TTF2 was ubiquitinated by APC/CCDH1 and targeted for proteasomal degradation. Interestingly, TTF2 bound to CDC20 and prevented MCC formation during normal mitosis. However, TTF2 was degraded by APC/CCDH1 when the cell encountered persistent G2/M arrest, which would release CDC20 and promote the assembly of MCC. Additionally, TTF2 was overexpressed in almost all solid tumors and correlated with poor survival in patients with several kinds of solid tumors. Thus, these findings establish a link between transcription termination and cell cycle regulation, revealing an unexpected mechanism by which TTF2 plays dual roles in mitosis by binding to CDH1 and CDC20 to balance the activation of APC/C and MCC.

Keywords:  anaphase-promoting complex/cyclosome; cell cycle arrest; mitotic checkpoint complex; transcription termination factor 2

DOI:  https://doi.org/10.1007/s11427-023-2538-2
J Cell Biol. 2025 Aug 04. pii: e202410206. [Epub ahead of print]224(8):

Structure of the microtubule-anchoring factor NEDD1 bound to the γ-tubulin ring complex.

Hugo Muñoz-Hernández, Yixin Xu, Aitor Pellicer Camardiel, Daniel Zhang, Allen Xue, Amol Aher, Ellie Walker, Florina Marxer, Tarun M Kapoor, Michal Wieczorek.

The γ-tubulin ring complex (γ-TuRC) is an essential multiprotein assembly that provides a template for microtubule nucleation. The γ-TuRC is recruited to microtubule-organizing centers (MTOCs) by the evolutionarily conserved attachment factor NEDD1. However, the structural basis of the NEDD1-γ-TuRC interaction is not known. Here, we report cryo-EM structures of NEDD1 bound to the human γ-TuRC in the absence or presence of the activating factor CDK5RAP2. We found that the C-terminus of NEDD1 forms a tetrameric α-helical assembly that contacts the lumen of the γ-TuRC cone and orients its microtubule-binding domain away from the complex. The structure of the γ-TuRC simultaneously bound to NEDD1 and CDK5RAP2 reveals that both factors can associate with the "open" conformation of the complex. Our results show that NEDD1 does not induce substantial conformational changes in the γ-TuRC but suggest that anchoring of γ-TuRC-capped microtubules by NEDD1 would be structurally compatible with the significant conformational changes experienced by the γ-TuRC during microtubule nucleation.

DOI: https://doi.org/10.1083/jcb.202410206
J Biol Chem. 2025 May 14. pii: S0021-9258(25)02085-X. [Epub ahead of print] 110235

The neural stem cell gene PAFAH1B1 controls cell cycle progression, DNA integrity, and paclitaxel sensitivity of triple-negative breast cancer cells.

Parth R Majmudar, Ruth A Keri.

  Triple-negative breast cancer (TNBC) is a highly aggressive disease with limited approved therapeutic options. The rapid growth and genomic instability of TNBC cells makes mitosis a compelling target, and a current mainstay of treatment is paclitaxel (Ptx), a taxane that stabilizes microtubules during mitosis. While initially effective, acquired resistance to Ptx is common, and other antimitotic therapies can be similarly rendered ineffective due to the development of resistance or systemic toxicity underscoring the need for new therapeutic approaches. Interrogating CRISPR essentiality screens in TNBC cell lines, we identified PAFAH1B1 (LIS1) as a potential vulnerability in this disease. PAFAH1B1 regulates mitotic spindle orientation, proliferation, and cell migration during neurodevelopment, yet little is known regarding its function in breast cancer. We found that suppressing PAFAH1B1 expression in TNBC cells reduces cell number, while non-malignant cells remain unaffected. PAFAH1B1 suppression alters cell cycle dynamics, increasing mitotic duration and accumulation of cells in the G2/M phase. The suppression of PAFAH1B1 expression also increases DNA double-strand breaks, indicating a requirement for sustained PAFAH1B1 expression to maintain the genomic integrity of TNBC cells. Lastly, PAFAH1B1 silencing substantially enhances these defects in cells that are taxane-resistant and sensitizes both parental and Ptx-resistant TNBC cells to Ptx. These results indicate that LIS1/PAFAH1B1 may be a novel target for the development of new anti-mitotic agents for treating TNBC, particularly in the context of paclitaxel resistance.

Keywords:  DNA damage; LIS1; PAFAH1B1; TNBC; breast cancer; mitosis; neural; paclitaxel; taxane; triple negative breast cancer

DOI:  https://doi.org/10.1016/j.jbc.2025.110235
Front Med (Lausanne). 2025 ;12 1550901

The multifaceted functions of SPC25 in cancer: from molecular pathways to targeted therapy.

Yigang Jin, Minjie Chen, Fei Chen, Zhaofeng Gao, Xiaoping Li, Lingyu Hu, Dandan Cai, Siqi Zhao, Zhengwei Song.

  Spindle Pole Body Component 25 (SPC25), a critical component of the NDC80 kinetochore complex, plays an essential role in maintaining chromosomal stability during mitosis. Recent studies have revealed its aberrant expression in various cancers, highlighting its potential as both a diagnostic biomarker and a therapeutic target. This review provides a comprehensive analysis of the molecular mechanisms underlying SPC25's involvement in tumorigenesis, including its regulation of cell cycle progression and interaction with key oncogenic pathways. Furthermore, we discuss its prognostic significance across different cancer types and its potential impact on therapy resistance. The emerging evidence underscores SPC25's multifaceted role in cancer biology, offering novel insights into its clinical applications. We conclude by exploring future research directions, emphasizing the need for in-depth studies to unravel the precise molecular functions of SPC25 and its therapeutic potential in cancer treatment.

Keywords:  NDC80 complex; SPC25; biomarker; cancer progression; therapeutic target

DOI:  https://doi.org/10.3389/fmed.2025.1550901
MicroPubl Biol. 2025 ;2025

The Schizosaccharomyces pombe nucleolar protein Nsk1 modulates rDNA silencing during interphase.

Jun-Song Chen, Sarah M Hanna, Alaina H Willet, Kathleen L Gould.

Schizosaccharomyces pombe Nsk1 acts at kinetochores during mitosis to prevent error-prone chromosome segregation and it is phosphoregulated by Cdk1 . The Clp1 / Cdc14 protein phosphatase, to which Nsk1 binds, reverses Cdk1-mediated phosphorylation of Nsk1 during anaphase. During interphase, Nsk1 localizes exclusively to the nucleolus and its function there is unknown. In this study, we examined whether Nsk1 shares functions in the nucleolus with other known Clp1 / Cdc14 phosphatase substrates that localize there. We found that Nsk1 participates in rRNA silencing but not rDNA segregation, rDNA transcription, or nucleolar organization.

DOI: https://doi.org/10.17912/micropub.biology.001616
J Cell Mol Med. 2025 May;29(10): e70318

The Overexpression of Collagen Receptor DDR1 is Associated With Chromosome Instability and Aneuploidy in Diffuse Large B-Cell Lymphoma.

Sandra Margielewska-Davies, Matthew Pugh, Eszter Nagy, Ciara I Leahy, Maha Ibrahim, Eanna Fennell, Aisling Ross, Jan Bouchal, Lauren Lupino, Matthew Care, Reuben Tooze, Gary Reynolds, Zbigniew Rudzki, Wenbin Wei, William Simmons, Vikki Rand, Kelly Hunter, John J Reynolds, Grant S Stewart, Katerina Bouchalova, Iona J Douglas, Katerina Vrzalikova, Paul G Murray.

  Although chronic inflammation is implicated in the pathogenesis of diffuse large B-cell lymphoma (DLBCL), the mechanisms responsible are unknown. We demonstrate that the overexpression of the collagen receptor, DDR1, correlates with reduced expression of spindle checkpoint genes, with three transcriptional signatures of aneuploidy and with a higher frequency of copy number alterations, pointing to a potential role for DDR1 in the acquisition of aneuploidy in DLBCL. In support of this, we found that collagen treatment of primary germinal centre B cells transduced with DDR1, not only partially recapitulated the aberrant transcriptional programme of DLBCL but also downregulated the expression of CENPE, a mitotic spindle that has a crucial role in preventing chromosome mis-segregation. CENPE expression was also downregulated following DDR1 activation in two B-cell lymphoma lines and was lost in most DDR1-expressing primary tumours. Crucially, the inhibition of CENPE and the overexpression of a constitutively activated DDR1 were able to induce aneuploidy in vitro. Our findings identify a novel mechanistic link between DDR1 signalling and chromosome instability in B cells and provide novel insights into factors driving aneuploidy in DLBCL.

Keywords:   TP53 ; CENPE; DDR1; DLBCL; aneuploidy; chromosome instability; collagen; mitotic spindle

DOI:  https://doi.org/10.1111/jcmm.70318
Cancer Gene Ther. 2025 May 16.

Structural regulation of PLK1 activity: implications for cell cycle function and drug discovery.

Danda Chapagai, Klaus Strebhardt, Michael D Wyatt, Campbell McInnes.

Polo Like Kinase 1 (PLK1), a key regulator of mitosis whose overexpression is often associated with poor survival rates in cancer, continues to be widely investigated as an oncology drug target with clinical trials evaluating second and third generation inhibitors. In addition to the conserved N-terminal kinase domain (KD), a unique characteristic of the Polo-Like kinase family is the C-terminal polo-box domain (PBD). The PBD contains a phosphopeptide binding site that recognizes substrates primed by other kinases and furthermore is responsible for subcellular localization of PLK1 to specific sites in the nucleus including centrosomes and kinetochores. Another role of the PBD is its regulatory ability through domain-domain interactions with the KD to maintain an autoinhibited state of PLK1. Insights into post translational modifications and the PBD - KD domain-domain association have been obtained and show that key events in PLK1 regulation include phosphosubstrate binding, T210 phosphorylation and engagement with the Bora protein. These can induce an open and active conformation where the domain-domain inhibitory interactions no longer dominate. Further regulatory events recently described include the interchange between monomeric and dimeric forms, which can also serve to inhibit or activate PLK1 during the cell cycle. Different oligomeric forms of PLK1, existing as homodimers and heterodimers with PLK2, have been identified and likely play context dependent roles. This review provides an overview of recent information describing structural and mechanistic insights into inhibition of PLK1 and the temporal and spatial requirements of its activation and regulation. It also covers recent insights into the conformational regulation of other members of the Polo-Like kinase family. The implications of the conformational regulation of PLK1 with respect to cell cycle function and drug discovery are significant and are therefore discussed in detail.

DOI: https://doi.org/10.1038/s41417-025-00907-7
Cancer Med. 2025 May;14(10): e70949

Centromere Protein F in Tumor Biology: Cancer's Achilles Heel.

Zitong Wan, Miaomiao Wen, Chunlong Zheng, Ying Sun, Yinxi Zhou, Yahui Tian, Shaowei Xin, Xuejiao Wang, Xiaohong Ji, Jie Yang, Yanlu Xiong, Yong Han.

   BACKGROUND: Centromere protein F (CENP-F) is an important nuclear matrix protein that regulates mitosis and the cell cycle, and plays a crucial role in recruiting spindle checkpoint proteins to maintain the accuracy of chromosome segregation. Studies have shown that CENP-F is closely involved in the pathogenesis of various diseases, particularly in the development and progression of malignant tumors, where it exhibits significant oncogenic activity.
OBJECTIVE: This review aims to systematically summarize the molecular structure, subcellular localization, expression regulation, intracellular transport mechanisms, biological functions, and carcinogenic mechanisms of CENP-F, as well as explore its potential value in cancer diagnosis and therapy.
METHODS: A comprehensive review and analysis of domestic and international research literature related to CENP-F were conducted, focusing on its role in tumorigenesis, development, and as a therapeutic target.
RESULTS: CENP-F acts as an oncogene and can maintain or promote the malignant phenotype of tumor cells through multiple mechanisms, including regulating signaling pathways related to cell proliferation and apoptosis, promoting metabolic reprogramming, angiogenesis, and tumor cell invasion and metastasis. Additionally, it plays an important role in the immune microenvironment and drug resistance regulation.
CONCLUSION: CENP-F plays a key, multidimensional role in tumor biology and is a promising therapeutic target for cancer treatment. Further exploration of the core pathways through which CENP-F regulates tumorigenesis and its potential for clinical translation is needed.

Keywords:  CENP‐F; mechanism; mitosis; tumor

DOI:  https://doi.org/10.1002/cam4.70949