bims-micesi 2025-07-06 papers

bims-micesi

Biomed News

on Mitotic cell signalling

Issue of 2025–07–06
seventeen papers selected by
Valentina Piano, Uniklinik Köln

The localisation and stability of the CENP-F protein are regulated by importin beta and microtubules in mitotic cells.
Centromeres in the thermotolerant yeast K. marxianus mediate attachment to a single microtubule.
CFAP100 couples microtubule glutamylation to spindle pole integrity in keratinocytes to promote epidermal development.
Disruption of spindle orientation and protein localization during asymmetric cleavage by pharmacological inhibition of serotonin signaling.
Condensin II activation by M18BP1.
Spindle morphology changes between meiosis and mitosis driven by CK2 regulation of the Ran pathway.
Chromosomal tethering and mitotic transcription promote ecDNA nuclear inheritance.
Anapc5 and Anapc7 as genetic modifiers of KIF18A function in fertility and mitotic progression.
Sphingolipid synthesis maintains nuclear membrane integrity and genome stability during cell division.
Mechanistic Design of Cell-Penetrating Disruptors for a Phospho-Dependent Interaction.
Unveiling how mitotic spindle orientation in 3D human colon organoids affects matrix displacements through a 4D study using DVC.
Chemically tunable FOXM1-D sensor revealed FOXM1 direct influence on cell cycle.
Intermediate Filament Protein BFSP2 Controls Spindle Formation via HSC70-Mediated Stabilization of CLTC During Oocyte meiosis.
Chromosome-specific centromeric patterns define the centeny map of the human genome.
PRC1 resists microtubule sliding in two distinct resistive modes due to variations in the separation between overlapping microtubules.
The multitalented TIP60 chromatin remodeling complex: wearing many hats in epigenetic regulation, cell division and diseases.
CENP-A and centromere evolution in equids.

Sci Rep. 2025 Jul 01. 15(1): 21125

The localisation and stability of the CENP-F protein are regulated by importin beta and microtubules in mitotic cells.

Ludovica Altieri, Michela Damizia, Paola Rovella, Vincenzo Costanzo, Morena Mancini, Patrizio Di Micco, Matteo Marzi, Daniela Trisciuoglio, Veronica Morea, Patrizia Lavia.

  CENP-F is a large protein acting in fundamental cell cycle processes, including nuclear envelope breakdown, mitotic microtubule function and chromosome segregation. These activities are mediated by specific CENP-F protein elements that interact with microtubules, motor proteins, centrosomes and kinetochores. CENP-F is then ubiquitinated and degraded in late mitosis. The C-terminal region of CENP-F contains regulatory elements, including a region required for nuclear localisation in interphase and a KEN box driving proteolysis in late mitosis. Here we show that CENP-F generates proximity ligation products with importin beta during mitosis. Furthermore, induction of importin beta overexpression influences CENP-F at two levels: it alters CENP-F mitotic localisation, promoting its accumulation at spindle poles and decreasing its association with kinetochores, and also causes its persistence in the late mitotic window in which CENP-F normally disappears, in a process that requires microtubule integrity and dynamics. These data implicate therefore importin beta in spatial and temporal control of CENP-F during mitosis, and uncover a functional interplay between CENP-F's ability to regulate mitotic microtubules and, in turn, a protective role of microtubules against CENP-F premature ubiquitination.

Keywords:  CENP-F; Importin beta; Kinetochores; Microtubules; Mitotic spindle poles; Protein stability

DOI:  https://doi.org/10.1038/s41598-025-96504-7
Chromosome Res. 2025 Jul 03. 33(1): 14

Centromeres in the thermotolerant yeast K. marxianus mediate attachment to a single microtubule.

Daniel J Barrero, Sabrine Hedouin, Yizi Mao, Charles L Asbury, Andrew B Stergachis, Eileen O'Toole, Sue Biggins.

  Eukaryotic chromosome segregation requires spindle microtubules to attach to chromosomes through kinetochores. The chromosomal locus that mediates kinetochore assembly is the centromere and is epigenetically specified in most organisms by a centromeric histone H3 variant called CENP-A. An exception to this is budding yeast, which have short, sequenced-defined point centromeres. In S. cerevisiae, a single CENP-A nucleosome is formed at the centromere and is sufficient for kinetochore assembly. The thermophilic budding yeast Kluyveromyces marxianus also has a point centromere, but its length is nearly double the S. cerevisiae centromere and the number of centromeric nucleosomes and kinetochore attachment sites is unknown. Purification of native kinetochores from K. marxianus yielded a mixed population, with one subpopulation that appeared to consist of doublets, making it unclear whether K. marxianus shares the same attachment architecture as S. cerevisiae. Here, we demonstrate that though the doublet kinetochores have a functional impact on kinetochore strength, kinetochore localization throughout the cell cycle appears conserved between these two yeasts. In addition, whole spindle electron tomography demonstrates that a single microtubule binds to each chromosome. Single-molecule nucleosome mapping analysis suggests the presence of a single centromeric nucleosome. Taken together, we propose that the K. marxianus point centromere assembles a single centromeric nucleosome that mediates attachment to one microtubule.

Keywords:   K. marxianus ; S. cerevisiae ; Centromere; Kinetochore; Microtubule; Spindle

DOI:  https://doi.org/10.1007/s10577-025-09772-4
Nat Commun. 2025 Jul 01. 16(1): 5591

CFAP100 couples microtubule glutamylation to spindle pole integrity in keratinocytes to promote epidermal development.

Shuang Sun, Zhaoying Wang, Zhaoyang Xu, Zhengfeng Wang, Jia Sun, Keke Li, Min Liu, Huijie Zhao, Peiwei Liu, Jun Zhou.

Despite the importance of keratinocytes in epidermal structure and function, the molecular mechanisms regulating the division of these cells remain poorly understood. Herein, we demonstrate an essential role for cilia and flagella associated protein 100 (CFAP100) in keratinocyte division. Cfap100-knockout mice display a thinner and transparent skin and an impaired epidermal barrier function. Depletion of CFAP100 in keratinocytes prolongs mitotic progression and compromises chromosome segregation. Molecular studies reveal that CFAP100 interacts with tubulin tyrosine ligase-like protein 13 (TTLL13) to maintain spindle pole integrity in dividing keratinocytes. Further analysis shows that CFAP100 recruits TTLL13 to the spindle pole to increase the glutamylation of spindle microtubules. Restoring microtubule glutamylation by overexpression of TTLL13 or depletion of cytosolic carboxypeptidase 5 remarkably rescues the spindle pole defects in CFAP100-depleted cells. These findings thus identify CFAP100 as a central link to couple microtubule glutamylation to spindle pole integrity in keratinocytes to promote epidermal development.

DOI: https://doi.org/10.1038/s41467-025-60677-6
Dev Biol. 2025 Jun 29. pii: S0012-1606(25)00184-8. [Epub ahead of print]526 26-37

Disruption of spindle orientation and protein localization during asymmetric cleavage by pharmacological inhibition of serotonin signaling.

Ayaki Nakamoto, Lisa M Nagy.

  Cell polarity directs the orientation and size of asymmetric cell division and the segregation of cell fate determinants, processes fundamental to development in all multicellular organisms. During asymmetric cleavage, the mitotic spindle aligns with a specified polarity of the mother cell, and cell fate determinants are distributed asymmetrically along the division axis. Here, we report that pharmacological inhibition of serotonin signaling during the 4-to-8-cell division in early embryos of the mud snail Ilyanassa obsoleta (currently known as Tritia obsoleta) disrupts the typical unequal division pattern. The oblique axis of division common to spirally cleaving molluscan embryos is altered, and the position of the mitotic spindle is randomized in these treatments. Mother cells generate abnormally large, atypically positioned daughter cells. We also find that, in normal embryos, proteins recognized by phosphorylated PKC and Bazooka/PAR-3 antibodies typically co-localize with the spindle apparatus to the apical cortex of each mother cell. These antigens subsequently segregate to the smaller of the two daughter cells. In embryos treated with the serotonin-receptor antagonist, the localization of these asymmetrically segregating proteins is randomized, and their localization is independent of spindle position. These results suggest that serotonin signaling coordinates spindle orientation, cortical polarity, and cell size in early asymmetric cleavages.

Keywords:  Asymmetric cell division; Ilyanassa obsoleta; Serotonin; Spindle orientation; Spiral cleavage

DOI:  https://doi.org/10.1016/j.ydbio.2025.06.025
Mol Cell. 2025 Jul 02. pii: S1097-2765(25)00543-X. [Epub ahead of print]

Condensin II activation by M18BP1.

Alessandro Borsellini, Duccio Conti, Erin E Cutts, Rebecca J Harris, Kai Walstein, Andrea Graziadei, Valentina Cecatiello, Tom F Aarts, Ren Xie, Abdelghani Mazouzi, Sushweta Sen, Claire Hoencamp, Richard Pleuger, Sabrina Ghetti, Lina Oberste-Lehn, Dongqing Pan, Tanja Bange, Judith H I Haarhuis, Anastassis Perrakis, Thijn R Brummelkamp, Benjamin D Rowland, Andrea Musacchio, Alessandro Vannini.

  Condensin I and II promote the drastic spatial rearrangement of the human genome upon mitotic entry. While condensin II is known to initiate this process in early mitosis, what triggers its activation and loading onto chromatin at this juncture remains unclear. Through genetic and proteomic approaches, we identify MIS18-binding protein 1 (M18BP1), a protein required to maintain centromere identity, as the elusive factor required for condensin II localization to chromatin. M18BP1 directly binds condensin II's CAP-G2 subunit. The condensin II antagonist MCPH1 also binds to CAP-G2 and outcompetes M18BP1 during interphase to maintain the genome in its uncondensed state. A switch from MCPH1 to M18BP1 at mitotic onset activates condensin II, thus promoting proper chromosome condensation. Regulation of this M18BP1-condensin interaction thus determines both the uncondensed state of the interphase genome and its compacted state in mitosis.

Keywords:  AlphA Fold II; M18BP1; SMC complexes; centromeres; chromosome condensation; condensin II; crosslinking mass spectrometry; cryo-EM; haploid genetics; mitosis

DOI:  https://doi.org/10.1016/j.molcel.2025.06.014
J Cell Biol. 2025 Aug 04. pii: e202407154. [Epub ahead of print]224(8):

Spindle morphology changes between meiosis and mitosis driven by CK2 regulation of the Ran pathway.

Helena Cantwell, Hieu Nguyen, Arminja N Kettenbach, Rebecca Heald.

The transition from meiotic divisions in the oocyte to embryonic mitoses is a critical step in animal development. Despite negligible changes to cell size and shape, following fertilization the small, barrel-shaped meiotic spindle is replaced by a large zygotic spindle that nucleates abundant astral microtubules at spindle poles. To probe underlying mechanisms, we applied a drug treatment approach using Ciona eggs and found that inhibition of casein kinase 2 (CK2) caused a shift from meiotic to mitotic-like spindle morphology with nucleation of robust astral microtubules, an effect reproduced in Xenopus egg cytoplasmic extracts. In both species, CK2 activity decreased at fertilization. Phosphoproteomic differences between Xenopus meiotic and mitotic extracts that also accompanied CK2 inhibition pointed to RanGTP-regulated factors as potential targets. Interfering with RanGTP-driven microtubule formation suppressed astral microtubule growth caused by CK2 inhibition. These data support a model in which CK2 activity attenuation at fertilization leads to activation of RanGTP-regulated microtubule effectors, inducing mitotic spindle morphology.

DOI: https://doi.org/10.1083/jcb.202407154
Mol Cell. 2025 Jul 01. pii: S1097-2765(25)00542-8. [Epub ahead of print]

Chromosomal tethering and mitotic transcription promote ecDNA nuclear inheritance.

Ashley Nichols, Yujin Choi, Roshan Xavier Norman, Yanyang Chen, Josefine Striepen, Eralda Salataj, Eléonore Toufektchan, Richard Koche, John Maciejowski.

  Extrachromosomal DNAs (ecDNAs) are circular DNAs that function in tumor progression and treatment resistance by amplifying oncogenes. ecDNAs lack centromeres and thus are not constrained to Mendelian segregation, enabling unequal and rapid accumulation within daughter cells. Despite intrinsic links to their oncogenic potential, the fidelity and mechanisms of ecDNA inheritance are poorly understood. Using human cancer cell lines, we show that ecDNAs are protected against cytosolic mis-segregation through mitotic clustering and tethering to mitotic chromosome ends. Accurate nuclear segregation of MYC-amplifying ecDNA depends on BRD4 transcriptional co-activation and mitotic transcription of the long non-coding RNA PVT1, which is frequently co-amplified with MYC. Disruption of ecDNA mitotic clustering through BRD4 inhibition, PVT1 depletion, or transcription inhibition causes ecDNA micronucleation and formation of homogeneously staining regions. We propose that nuclear inheritance of ecDNA is facilitated by an RNA-based mechanism that clusters ecDNA during mitosis and protects against cytosolic mis-segregation and chromosomal reintegration.

Keywords:  MYC; PVT1; ecDNA; genome amplification; homogeneously staining region; micronuclei

DOI:  https://doi.org/10.1016/j.molcel.2025.06.013
Sci Rep. 2025 Jul 02. 15(1): 23046

Anapc5 and Anapc7 as genetic modifiers of KIF18A function in fertility and mitotic progression.

Carleigh Nesbit, Whitney Martin, Anne Czechanski, Candice Byers, Narayanan Raghupathy, Ardian Ferraj, Jason Stumpff, Laura Reinholdt.

The kinesin family member 18 A (KIF18A) is an essential regulator of microtubule dynamics and chromosome alignment during mitosis. Functional dependency on KIF18A varies by cell type and genetic context but the heritable factors that influence this dependency remain unknown. To address this, we took advantage of the variable penetrance observed in different mouse strain backgrounds to screen for loci that modulate germ cell depletion in the absence of KIF18A. We found a significant association at a Chr5 locus where anaphase promoting complex subunits 5 (Anapc5) and 7 (Anapc7) were the top candidate genes. We found that both genes were differentially expressed in a sensitive strain background when compared to resistant strain background at key timepoints in gonadal development. We also identified a novel retroviral insertion in Anapc7 that may in part explain the observed expression differences. In cell line models, we found that depletion of KIF18A induced mitotic arrest, which was partially rescued by co-depletion of ANAPC7 (APC7) and exacerbated by co-depletion of ANAPC5 (APC5). These findings suggest that differential expression and activity of Anapc5 and Anapc7 may influence sensitivity to KIF18A depletion in germ cells and CIN cells, with potential implications for optimizing antineoplastic therapies.

DOI: https://doi.org/10.1038/s41598-025-08766-w
J Cell Biol. 2025 Aug 04. pii: e202407209. [Epub ahead of print]224(8):

Sphingolipid synthesis maintains nuclear membrane integrity and genome stability during cell division.

Sunyoung Hwang, William Russo, Jaylah Cormier, Jillian Johnson, Sara Martin, Marica Rosaria Ippolito, Sara Cordone, Rui Li, Lihua Julie Zhu, Stefano Santaguida, Eduardo M Torres.

Lipid synthesis must be precisely regulated to support membrane growth and organelle biogenesis during cell division, yet little is known about how this process is coordinated with other cell cycle events. Here, we show that de novo synthesis of sphingolipids during the S and G2 phases of the cell cycle is essential to increasing nuclear membranes. Indeed, the products of serine palmitoyltransferase (SPT), long-chain bases, localize to the nucleus and are integral components of nuclear membranes in yeast and human cells. Importantly, inhibition of SPT fails to induce cell cycle arrest, causing nuclear membrane collapse and loss of viability in yeast cells. In human cells, this causes abnormal nuclear morphology and genomic instability, evidenced by the increased incidence of nuclear blebs, micronuclei, anaphase bridges, and multipolar mitosis. These results indicate that dysregulated cell division under low sphingolipid availability can drive several disease-associated phenotypes, including aberrant nuclear morphologies and genomic instability.

DOI: https://doi.org/10.1083/jcb.202407209
Res Sq. 2025 Jun 17. pii: rs.3.rs-6862805. [Epub ahead of print]

Mechanistic Design of Cell-Penetrating Disruptors for a Phospho-Dependent Interaction.

Vanda Gunning, Matthew Batchelor, Krista K Alexander, Martin Walko, Selena G Burgess, Stephen J Royle, Eileen J Kennedy, Richard Bayliss.

The complex formed by transforming acidic coiled coil 3 (TACC3) and clathrin heavy chain (CHC) enhances mitotic spindle stability and strength by cross-linking microtubules. The interaction is dependent on phosphorylation of TACC3 at S558 by Aurora-A. Previously, we elucidated the structural basis of the TACC3/CHC interaction, which is driven by hydrophobic residues on both proteins and the formation of an α-helix in TACC3 that docks into the helical repeats of CHC. Here we find that this phosphorylation event plays an unusual role in the protein-protein interaction; rather than direct bond formation, the phosphorylated residue acts by overcoming an inherent electrostatic repulsion between K507 of CHC and basic residues in TACC3. Leveraging this insight, we optimized the sequence using peptide arrays to develop a hydrocarbon-stapled peptide (SP TACC3) that binds CHC with over a hundred-fold higher affinity than the parental TACC3 peptide, effectively disrupting the native interaction. The crystal structure of the SP TACC3/CHC complex reveals the basis for the enhanced interaction and highlights the contribution of additional polar and hydrophobic interactions. SP TACC3 efficiently penetrates cells and displaces TACC3 from the mitotic spindle, causing a delay in mitotic progression in two out of three cancer cell lines. This work showcases the novel application of hydrocarbon-stapled peptides to disrupt the TACC3/CHC protein-protein interaction in a cellular context, highlighting the potential of targeting this interface for future cancer therapies.

DOI: https://doi.org/10.21203/rs.3.rs-6862805/v1
Sci Rep. 2025 Jul 01. 15(1): 22052

Unveiling how mitotic spindle orientation in 3D human colon organoids affects matrix displacements through a 4D study using DVC.

L Magne, T Pottier, D Michel, J Laussu, D Bonnet, L Alric, S Segonds, G Recher, F Bugarin, A Ferrand.

  Cell division is a major event in tissue homeostasis, enabling renewal and regeneration. In human colon, vertical division is mainly observed in the stem cell compartment while horizontal division is more frequent in the progenitor transit amplifying zone. To study cell division, the human colon epithelium represents a relevant model due to its rapid renewal and high number of mitoses. Studying live mechanical interactions between the epithelium and its matrix in vivo is challenging due to the lack of suitable methods. Colon organoids seeded in Matrigel are good models because they recapitulate the organization and properties of tissue architecture. This culture set-up allows to study the displacements of the matrix around the organoid. We studied the impact of cell division within the human colonic epithelium on the extracellular matrix. We validated an original experimental and analytical process with 3D time-lapse confocal microscopy to follow cell division and matrix displacements, on which we performed a 4D Digital Volume Correlation. Depending on the orientation of the mitotic spindle, cell division affects the matrix differently. Vertical division causes a predominantly uniaxial displacement of the matrix, while horizontal division involves a multiaxial and wider displacement.

Keywords:  4D digital volume correlation; 4D displacements; Cell division; Extracellular matrix; Organoid

DOI:  https://doi.org/10.1038/s41598-025-04156-4
J Cell Sci. 2025 Jun 30. pii: jcs.263749. [Epub ahead of print]

Chemically tunable FOXM1-D sensor revealed FOXM1 direct influence on cell cycle.

Kriengkrai Phongkitkarun, Porncheera Chusorn, Maliwan Kamkaew, Supawan Jamnongsong, Eric W-F Lam, Chamras Promptmas, Somponnat Sampattavanich.

  Forkhead box protein M1 (FOXM1) is a transcription factor required for the G2/M transition and is frequently upregulated in cancers, promoting tumor progression and therapy resistance. However, its dynamic regulation throughout the cell cycle remains unclear. We developed a tunable FOXM1-DHFR (FOXM1-D) sensor in non-malignant MCF10A cells, enabling real-time monitoring and manipulation of FOXM1 levels. Using trimethoprim (TMP) to stabilize FOXM1-D, we quantified its production, degradation, and nuclear translocation during G1 and G2 phases. Overexpression of FOXM1-D accelerated cell division in G1 and S phases but did not affect G2-synchronized cells. Notably, 70%-90% of FOXM1-D overexpressing cells were arrested after the first division, whereas those with timely degradation allowed a second division. Sustained FOXM1-D overexpression induced cell cycle arrest in daughter cells, highlighting the role of FOXM1 kinetics in determining cell fate. Sustained FOXM1-D upregulates p21, triggering G1 arrest. Thus, targeting FOXM1 exploits its dual capacity to induce oncogene-induced senescence (OIS) or suppress mitotic entry. Our study provides a basis for precision therapies that align interventions with FOXM1 kinetics to improve outcomes in FOXM1-driven tumors.

Keywords:  Cell Cycle; Cell Fate Decision; FOXM1; Live-cell dynamics; Modeling; Tunable Biosensors

DOI:  https://doi.org/10.1242/jcs.263749
Adv Sci (Weinh). 2025 Jul 02. e06639

Intermediate Filament Protein BFSP2 Controls Spindle Formation via HSC70-Mediated Stabilization of CLTC During Oocyte meiosis.

Yu Li, Zihao Zhang, Yu Zhang, Bo Xiong.

  As a major component of the cytoskeleton, intermediate filaments are generally considered to play a supporting role in mitotic cells. They also take part in the regulation of cell motility, proliferation, differentiation, and apoptosis. However, their specific functions during meiosis are largely unknown. Here, a unique role of an intermediate filament protein beaded filament structural protein 2 (BFSP2) is reported, which is predominantly expressed in lens fiber epithelial cells, as a spindle formation controller in oocyte meiosis. BFSP2 is constantly expressed during oocyte meiotic maturation, and specifically distributed on the spindle apparatus at metaphase I (MI) and metaphase II (MII) stages. Depletion of BFSP2 resulted in the meiotic arrest at MI stage due to the aberrant spindle assembly-induced spindle assembly checkpoint activation. Depletion of BFSP2 also led to incorrect kinetochore-microtubule attachments and the occurrence of aneuploidy in oocytes. Mechanistically, immunoprecipitation combined with mass spectrometry analysis identified clathrin heavy chain 1 (CLTC) as the downstream mediator of BFSP2 during meiotic spindle assembly. It is further determined that BFSP2 recruited the molecular chaperone heat shock cognate protein 70 (HSC70) to the spindle apparatus for stabilizing CLTC, and thus driving the spindle formation. In summary, these findings uncover a noncanonical function of the intermediate filament protein BFSP2 as a spindle assembly controller in oocyte meiosis.

Keywords:  BFSP2; CLTC; HSC70; intermediate filaments; oocyte meiosis; spindle assembly

DOI:  https://doi.org/10.1002/advs.202506639
Science. 2025 Jul 03. 389(6755): eads3484

Chromosome-specific centromeric patterns define the centeny map of the human genome.

Luca Corda, Simona Giunta.

Centromeres are epigenetically specified by distinct chromatin, whereas their DNA varies between species and individuals. This extensive sequence divergence makes comparative analyses between centromeres challenging. In this study, we identified a chromosome-specific architectural pattern across the human genome, defined by the conserved spacing of a functionally relevant centromeric DNA motif. The distribution of these sites along chromosome arms constitutes the human "centeny map." By using a custom Genomic Centromere Profiling (GCP) pipeline, we leveraged the motif's position, orientation, and organization to construct structural models that enable reclassification of human chromosomal clusters, detection of centromere expansion, and identification of structural variants and misassembled regions. The high-resolution maps derived from this pattern not only provide a framework for comparative analysis of centromeres across evolution and disease but also offer a new dimension for chromosome annotation, assembly, and characterization.

DOI: https://doi.org/10.1126/science.ads3484
Mol Biol Cell. 2025 Jul 02. mbcE25060288

PRC1 resists microtubule sliding in two distinct resistive modes due to variations in the separation between overlapping microtubules.

Daniel Steckhahn, Shane A Fiorenza, Ellinor Tai, Scott Forth, Peter R Kramer, Meredith Betterton.

Crosslinked cytoskeletal filament networks provide cells with a mechanism to regulate cellular mechanics and force transmission. An example in the microtubule cytoskeleton is mitotic spindle elongation. The three-dimensional geometry of these networks, including the overlap length and lateral microtubule spacing, likely controls how forces can be regulated, but how these parameters evolve during filament sliding is unknown. Recent evidence suggests that the crosslinker PRC1 can resist microtubule sliding by two distinct modes: a braking mode and a less resistive coasting mode. To explore how molecular-scale mechanisms influence network geometry in this system, we developed a computational model of sliding microtubule pairs crosslinked by PRC1 that reproduces the experimentally observed braking and coasting modes. Surprisingly, we found that the braking mode was associated with a substantially smaller lateral separation between the crosslinked microtubules than the coasting mode. This closer separation aligns the PRC1-mediated forces against sliding, increasing the resistive PRC1 force and dramatically reducing sliding speed. The model also finds an emergent similar average sliding speed due to PRC1 resistance, because higher initial sliding speed favors the transition to braking. Together, our results highlight the importance of the three-dimensional geometric relationships between crosslinkers and microtubules.

DOI: https://doi.org/10.1091/mbc.E25-06-0288
Epigenetics Chromatin. 2025 Jul 02. 18(1): 40

The multitalented TIP60 chromatin remodeling complex: wearing many hats in epigenetic regulation, cell division and diseases.

Maria Virginia Santopietro, Diego Ferreri, Yuri Prozzillo, Patrizio Dimitri, Giovanni Messina.

  The TIP60 complex is an evolutionarily conserved, multifunctional chromatin remodeling complex involved in critical cellular processes, including DNA repair, transcription regulation, and cell cycle control. Although its molecular organization and functions have been extensively studied, a comparative synthesis of its context-specific roles across evolutionarily distant species and pathological conditions is important to fully grasp its biological and clinical significance. In this review, we provide an integrative overview of the TIP60 complex, emphasizing its composition and conserved functions in Homo sapiens and Drosophila melanogaster, with comparative insights from plant systems. We explore how TIP60 complex dysregulation contributes to the molecular pathology of cancer and neurodevelopmental disorders, highlighting recent mechanistic insights. We also examine the emerging interplay between TIP60 complex subunits and long non-coding RNAs, which are increasingly recognized as pivotal regulators of genome accessibility and transcriptional programs. Finally, in this intriguing scenario, we highlight the non-canonical functions of the TIP60 complex in mitosis and cytokinesis, underscoring its moonlighting roles in maintaining genomic and cellular integrity, beyond its established contribution to epigenetic regulation. By connecting these diverse aspects, our review aims to provide an integrated perspective on the TIP60 complex and its expanding functional landscape in health and disease.

Keywords:  Cell division; Chromatin remodeling; Diseases; LncRNAs; Moonlighting proteins; TIP60 complex

DOI:  https://doi.org/10.1186/s13072-025-00603-8
Chromosome Res. 2025 Jun 30. 33(1): 13

CENP-A and centromere evolution in equids.

Eleonora Cappelletti, Francesca M Piras, Marialaura Biundo, Rebecca R Bellone, Carrie J Finno, Ted S Kalbfleisch, Jessica L Petersen, Solomon G Nergadze, Elena Giulotto.

  While the centromeric function is conserved and epigenetically specified by CENP-A, centromeric DNA, typically composed of satellite repeats, is highly divergent and rapidly evolving. In the species of the genus Equus (horses, asses and zebras), also known as equids, the numerous centromeres devoid of satellite repeats enabled us to carry out molecular analysis of centromeric chromatin establishing a unique model system for mammalian centromere biology. In this review, after a brief description of the rapid evolution of equids, we outline one of our most relevant initial discoveries: the position of CENP-A binding domains is variable among individuals giving rise to epialleles which are inherited as Mendelian traits. This positional variability was recently confirmed in human centromeres whose repetitive DNA organization could be analyzed thanks to telomere-to-telomere (T2T) genome assemblies. Another unexpected observation was that, in equids, CENP-B does not bind the centromeric core and is uncoupled from CENP-A and CENP-C. CENP-B is absent from the majority of chromosomes while the CENP-B binding DNA sequence (CENP-B box) is comprised within a satellite that is localized at pericentromeric or terminal positions. Finally, comparative molecular and cytogenetic analyses of satellite-free centromeres revealed that the birth of neocentromeres during the evolution of this genus occurred through two alternative mechanisms: centromere repositioning and Robertsonian fusion. These events played a key role in karyotype reshuffling and speciation. Investigating centromere organization in equids provided new insights into the complexity of centromere organization across the vast biodiversity of the mammalian world, where the majority of species remain understudied.

Keywords:  CENP-A; CENP-B; Centromere; Genus Equus ; Karyotype evolution; Satellite DNA

DOI:  https://doi.org/10.1007/s10577-025-09773-3