bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2025–03–16
ten papers selected by
Valentina Piano, Uniklinik Köln
  1. Mps1 kinase functions in mitotic spindle assembly and error correction.
  2. Mitotic spindle membranes.
  3. The PP2A-B56 Binding Site LxxIxE Contributes to Asp-Mediated Spindle Pole Stability.
  4. Canonical Hedgehog Signaling Controls Astral Microtubules and Mitotic Spindle Orientation in Neural Progenitors and iPSCs.
  5. HIV-1 Vif disrupts phosphatase feedback regulation at the kinetochore, leading to a pronounced pseudo-metaphase arrest.
  6. The DEAD-box helicase eIF4A1/2 acts as RNA chaperone during mitotic exit enabling chromatin decondensation.
  7. An atlas of RNA-dependent proteins in cell division reveals the riboregulation of mitotic protein-protein interactions.
  8. The Kinesin-14 Tail: Dual microtubule binding domains drive spindle morphogenesis through tight microtubule cross-linking and robust sliding.
  9. Copper is essential for cyclin B1-mediated CDK1 activation.
  10. Polarity-guided uneven mitotic divisions control brassinosteroid activity in proliferating plant root cells.
  1. Trends Biochem Sci. 2025 Mar 12. pii: S0968-0004(25)00032-5. [Epub ahead of print]
    Mps1 kinase functions in mitotic spindle assembly and error correction.
    Victor M Bolanos-Garcia.
      The protein kinase Mps1 (also known as TTK) is a central component of the mitotic spindle assembly checkpoint (SAC), an essential self-monitoring system of the eukaryotic cell cycle that ensures accurate chromosome segregation by delaying the onset of anaphase until all chromosomes are properly bioriented on the mitotic spindle. Mps1 kinase is an important upstream regulator of the SAC and its recruitment to kinetochores critical for initiating SAC signaling. This review discusses the current understanding of Mps1 essential functions in the SAC, the emerging details of Mps1 role in error correction to safeguard genome stability, and the therapeutic potential of Mps1 inhibition for the treatment of cancer types associated with aberrant SAC signaling and chromosome segregation defects.
    Keywords:  Mps1/TTK kinase; chromosome segregation regulation; chromosome-microtubule attachment; kinase inhibitors; kinetochore complexes; spindle assembly checkpoint (SAC)
    DOI:  https://doi.org/10.1016/j.tibs.2025.02.005
  2. Mol Biol Cell. 2025 Apr 01. 36(4): re1
    Mitotic spindle membranes.
    Jonathan M Scholey.
      The mitotic spindle, which uses microtubules (MTs) and MT-based motor proteins to separate sister chromosomes prior to cell division, contains abundant membranes, organelles, and protein assemblies derived from the familiar interphase intracellular membrane network. In this essay, mainly with reference to selected animal and fungal cells, I summarize current ideas about the reciprocal functional relationship between these mitotic spindle-associated membranes and the spindle MT cytoskeleton, in which; 1) spindle membranes control the composition, Ca++ ion concentration and mechanical performance of the spindle MT cytoskeleton; and conversely 2) the spindle MT cytoskeleton contributes to membrane/organelle partitioning and inheritance during cell division and serves as a reservoir of membranes, organelles, and vesicles for delivery to the interphase cytoplasm, plasma membrane, and cleavage furrow.
    DOI:  https://doi.org/10.1091/mbc.E24-10-0475
  3. Cytoskeleton (Hoboken). 2025 Mar 12.
    The PP2A-B56 Binding Site LxxIxE Contributes to Asp-Mediated Spindle Pole Stability.
    Margaux Quiniou, Maria C Burns, Aynsley McDermott, Karolina Jaworek, Stacey J Scott, James G Wakefield, Lori Borgal.
      The organization of microtubules into a mitotic spindle is critical for animal cell proliferation and involves the cooperation of hundreds of proteins whose molecular roles and regulation are not fully understood. The protein product of the Drosophila gene abnormal spindle, Asp, is a microtubule-associated protein required for correct mitotic spindle formation. To better understand the contribution of Asp to microtubule organization during spindle formation, we reverse-engineered flies to express a version of Asp (AspLIE), predicted to have lost its ability to bind the phosphatase trimer PP2A-B56. We demonstrated that the AspLIE mutation reduced an interaction with the Drosophila PP2A-B56 regulatory subunit Widerborst (Wdb), as well as other proteins with known roles in spindle formation. AspLIE flies exhibited less robust microtubule minus-end cohesion at neural stem cell spindle poles, which was accompanied by a substantial developmental delay but no microcephaly. Predictive structural modeling suggests that the presence of Wdb alters the conformation of an Asp interaction with a tubulin dimer in a manner similar to that of the AspLIE mutation. Protein localization in the Drosophila embryo, in addition to in vitro microtubule organization experiments, suggests that a role of PP2A may be to prevent Asp from contributing to microtubule cross-linking at spindle microtubule plus ends. Together, these findings add new insights to mechanisms underlying microtubule organization within the mitotic spindle.
    Keywords:   drosophila ; PP2A; Wdb; asp; microtubule; mitosis; spindle
    DOI:  https://doi.org/10.1002/cm.22013
  4. bioRxiv. 2025 Feb 25. pii: 2025.02.23.639780. [Epub ahead of print]
    Canonical Hedgehog Signaling Controls Astral Microtubules and Mitotic Spindle Orientation in Neural Progenitors and iPSCs.
    Fengming Liu, Anna Medyukhina, Kris M Olesen, Abbas Shirinifard, Hongjian Jin, Lei Li, Marina Mapelli, Khaled Khairy, Young-Goo Han.
      Mitotic spindle orientation is crucial for cell fate determination and tissue organization. Although the intracellular machinery governing spindle orientation is well characterized, whether and how secreted factors, such as morphogens, regulate this process remains poorly understood. This study investigated the role of Hedgehog (HH) signaling in modulating mitotic spindle orientation in neural progenitor cells and in induced pluripotent stem cells (iPSCs). Time-lapse microscopy of cerebral organoids and iPSCs revealed that HH signaling increases the angle of the mitotic spindle relative to the apical surface, prolongs mitosis, and enhances spindle rotation. Mechanistically, HH signaling reduces both the number and the length of astral microtubules, key regulators of spindle orientation. This reduction correlates with increased spindle angle in iPSCs. Furthermore, we show that canonical HH signaling, involving GLI-dependent transcriptional regulation, contributes to these effects. RNA sequencing and gene set enrichment analysis (GSEA) revealed that HH signaling upregulates genes associated with microtubule depolymerization, suggesting a transcriptional mechanism by which HH signaling influences astral microtubule dynamics and, consequently, mitotic spindle orientation. These findings highlight a novel link between a morphogen, transcriptional regulation, and the control of mitotic spindle orientation, with implications for development and tissue homeostasis.
    DOI:  https://doi.org/10.1101/2025.02.23.639780
  5. Elife. 2025 Mar 13. pii: RP101136. [Epub ahead of print]13
    HIV-1 Vif disrupts phosphatase feedback regulation at the kinetochore, leading to a pronounced pseudo-metaphase arrest.
    Dhaval Ghone, Edward L Evans, Madison Bandini, Kaelyn G Stephenson, Nathan M Sherer, Aussie Suzuki.
      Virion Infectivity Factor (Vif) of the Human Immunodeficiency Virus type 1 (HIV-1) targets and degrades cellular APOBEC3 proteins, key regulators of intrinsic and innate antiretroviral immune responses, thereby facilitating HIV-1 infection. While Vif's role in degrading APOBEC3G is well-studied, Vif is also known to cause cell cycle arrest, but the detailed nature of Vif's effects on the cell cycle has yet to be delineated. In this study, we employed high-temporal resolution single-cell live imaging and super-resolution microscopy to monitor individual cells during Vif-induced cell cycle arrest. Our findings reveal that Vif does not affect the G2/M boundary as previously thought. Instead, Vif triggers a unique and robust pseudo-metaphase arrest, distinct from the mild prometaphase arrest induced by Vpr. During this arrest, chromosomes align properly and form the metaphase plate, but later lose alignment, resulting in polar chromosomes. Notably, Vif, unlike Vpr, significantly reduces the levels of both Protein Phosphatase 1 (PP1) and 2 A (PP2A) at kinetochores, which regulate chromosome-microtubule interactions. These results unveil a novel role for Vif in kinetochore regulation that governs the spatial organization of chromosomes during mitosis.
    Keywords:  HIV; Vif; Vpr; cell cycle; infectious disease; microbiology; mitosis; protein phosphatase; viruses
    DOI:  https://doi.org/10.7554/eLife.101136
  6. Nat Commun. 2025 Mar 11. 16(1): 2434
    The DEAD-box helicase eIF4A1/2 acts as RNA chaperone during mitotic exit enabling chromatin decondensation.
    Ramona Jühlen, Sabine C Wiesmann, Anja Scheufen, Thilo Stausberg, Isabel Braun, Chantal Strobel, Carmen Llera-Brandt, Sabrina Rappold, Rabia Suluyayla, Marianna Tatarek-Nossol, Birgitt Lennartz, Hongqi Lue, Maximilian W G Schneider, Juan-Felipe Perez-Correa, Daniel Moreno-Andrés, Wolfram Antonin.
      During mitosis, chromosomes condense and decondense to segregate faithfully and undamaged. The exact molecular mechanisms are not well understood. We identify the DEAD-box helicase eIF4A1/2 as a critical factor in this process. In a cell-free condensation assay eIF4A1/2 is crucial for this process, relying on its RNA-binding ability but not its ATPase activity. Reducing eIF4A1/2 levels in cells consistently slows down chromatin decondensation during nuclear reformation. Conversely, increasing eIF4A1/2 concentration on mitotic chromosomes accelerates their decondensation. The absence of eIF4A1/2 affects the perichromatin layer, which surrounds the chromosomes during mitosis and consists of RNA and mainly nucleolar proteins. In vitro, eIF4A1/2 acts as an RNA chaperone, dissociating biomolecular condensates of RNA and perichromatin proteins. During mitosis, the chaperone activity of eIF4A1/2 is required to regulate the composition and fluidity of the perichromatin layer, which is crucial for the dynamic reorganization of chromatin as cells exit mitosis.
    DOI:  https://doi.org/10.1038/s41467-025-57592-1
  7. Nat Commun. 2025 Mar 08. 16(1): 2325
    An atlas of RNA-dependent proteins in cell division reveals the riboregulation of mitotic protein-protein interactions.
    Varshni Rajagopal, Jeanette Seiler, Isha Nasa, Simona Cantarella, Jana Theiss, Franziska Herget, Bianca Kaifer, Melina Klostermann, Rainer Will, Martin Schneider, Dominic Helm, Julian König, Kathi Zarnack, Sven Diederichs, Arminja N Kettenbach, Maïwen Caudron-Herger.
      Ribonucleoprotein complexes are dynamic assemblies of RNA with RNA-binding proteins, which modulate the fate of RNA. Inversely, RNA riboregulates the interactions and functions of the associated proteins. Dysregulation of ribonucleoprotein functions is linked to diseases such as cancer and neurological disorders. In dividing cells, RNA and RNA-binding proteins are present in mitotic structures, but their impact on cell division remains unclear. By applying the proteome-wide R-DeeP strategy to cells synchronized in mitosis versus interphase integrated with the RBP2GO knowledge, we provided an atlas of RNA-dependent proteins in cell division, accessible at R-DeeP3.dkfz.de. We uncovered AURKA, KIFC1 and TPX2 as unconventional RNA-binding proteins. KIFC1 was identified as a new substrate of AURKA, and new TPX2-interacting protein. Their pair-wise interactions were RNA dependent. In addition, RNA stimulated AURKA kinase activity and stabilized its conformation. In this work, we highlighted riboregulation of major mitotic factors as an additional complexity level of cell division.
    DOI:  https://doi.org/10.1038/s41467-025-57671-3
  8. bioRxiv. 2025 Feb 26. pii: 2025.02.25.640188. [Epub ahead of print]
    The Kinesin-14 Tail: Dual microtubule binding domains drive spindle morphogenesis through tight microtubule cross-linking and robust sliding.
    Stephanie C Ems-McClung, MacKenzie Cassity, Anjaly Prasannajith, Claire E Walczak.
      Proper spindle assembly requires the Kinesin-14 family of motors to organize microtubules (MTs) into the bipolar spindle by cross-linking and sliding anti-parallel and parallel MTs through their motor and tail domains. How they mediate these different activities is unclear. We identified two MT binding domains (MBD1 and MBD2) within the Xenopus Kinesin-14 XCTK2 tail and found that MBD1 MT affinity was weaker than MBD2. Comparable to full-length GFP-XCTK2 wild-type protein (GX-WT), GFP-XCTK2 containing the MBD1 mutations (GX-MBD1 mut ) stimulated spindle assembly, localized well on the spindle, and formed narrow spindles. In contrast, GX-MBD2 mut only partially stimulated spindle assembly, localized weakly on the spindle, and formed shorter spindles. Biochemical reconstitution of MT cross-linking and sliding demonstrated that GX-MBD2 mut slid anti-parallel MTs faster than GX-WT and GX-MBD1 mut . However, GX-WT and GX-MBD1 mut statically cross-linked the majority of parallel MTs, whereas GX-MBD2 mut equally slid and statically cross-linked parallel MTs without affecting their sliding velocity. These results provide a mechanism by which the two different MT binding domains in the Kinesin-14 tail balance anti-parallel MT sliding velocity (MBD1) and tight parallel MT cross-linking (MBD2), which are important for spindle assembly and localization, and provide a basis for characterizing how molecular motors organize MTs within the spindle.
    Significance Statement: Spindle assembly and organization utilize molecular motors that cross-link and slide anti-parallel and parallel microtubules. How individual motors moderate both active sliding and static cross-linking is not understood.Using biochemical reconstitution, the authors determined that the Kinesin-14 tail contains two independent microtubule binding domains. MBD1 with weaker microtubule binding facilitates faster anti-parallel microtubule sliding, whereas the stronger MBD2 mediates tight parallel microtubule cross-linking, which was important for spindle assembly.These findings provide a mechanism for how Kinesin-14s differentially control microtubule sliding and cross-linking and provide insight into how molecular motors can mediate the dynamic organization of microtubules in the spindle.
    DOI:  https://doi.org/10.1101/2025.02.25.640188
  9. Nat Commun. 2025 Mar 07. 16(1): 2288
    Copper is essential for cyclin B1-mediated CDK1 activation.
    Jiaru Wang, Dian Yang, Hai-Fan Yu, Jing Jin, Yuzhe Nie, Sihua Zhang, Weiwei Ren, Zihan Ge, Zhuo Zhang, Xinghong Ma, Shaojun Dai, Guangchao Sui, Chun-Bo Teng.
      Cyclin-dependent kinase 1 (CDK1) is the pivotal kinase responsible for initiating cell division. Its activation is dependent on binding to regulatory cyclins, such as CCNB1. Our research demonstrates that copper binding to both CDK1 and CCNB1 is essential for activating CDK1 in cells. Mutations in the copper-binding amino acids of either CDK1 or CCNB1 do not disrupt their interaction but are unable to activate CDK1. We also reveal that CCNB1 facilitates the transfer of copper from ATOX1 to CDK1, consequently activating its kinase function. Disruption of copper transfer through the ATOX1-CCNB1-CDK1 pathway can impede CDK1 activation and halt cell cycle progression. In summary, our findings elucidate a mechanism through which copper promotes CDK1 activation and the G2/M transition in the cell cycle. These results could provide insight into the acquisition of proliferative properties associated with increased copper levels in cancer and offer targets for cancer therapy.
    DOI:  https://doi.org/10.1038/s41467-025-57538-7
  10. Cell. 2025 Mar 06. pii: S0092-8674(25)00196-5. [Epub ahead of print]
    Polarity-guided uneven mitotic divisions control brassinosteroid activity in proliferating plant root cells.
    Nemanja Vukašinović, Che-Wei Hsu, Marco Marconi, Shaopeng Li, Christopher Zachary, Rachel Shahan, Pablo Szekley, Ziv Aardening, Isabelle Vanhoutte, Qian Ma, Lucrezia Pinto, Pavel Krupař, Nathan German, Jingyuan Zhang, Claire Simon-Vezo, Jessica Perez-Sancho, Pepe Cana Quijada, Qianzi Zhou, Laura R Lee, Jianghua Cai, Emmanuelle M Bayer, Matyáš Fendrych, Elisabeth Truernit, Yu Zhou, Sigal Savaldi-Goldstein, Krzysztof Wabnik, Trevor M Nolan, Eugenia Russinova.
      Brassinosteroid hormones are positive regulators of plant organ growth, yet their function in proliferating tissues remains unclear. Here, through integrating single-cell RNA sequencing with long-term live-cell imaging of the Arabidopsis root, we reveal that brassinosteroid activity fluctuates throughout the cell cycle, decreasing during mitotic divisions and increasing during the G1 phase. The post-mitotic recovery of brassinosteroid activity is driven by the intrinsic polarity of the mother cell, resulting in one daughter cell with enhanced brassinosteroid signaling, while the other supports brassinosteroid biosynthesis. The coexistence of these distinct daughter cell states during the G1 phase circumvents a negative feedback loop to facilitate brassinosteroid production while signaling increases. Our findings uncover polarity-guided, uneven mitotic divisions in the meristem, which control brassinosteroid hormone activity to ensure optimal root growth.
    Keywords:  brassinosteroids; cell cycle; cell division; cell polarity; live-cell imaging; root meristem; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.cell.2025.02.011
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