bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2024–09–22
nine papers selected by
Valentina Piano, Uniklinik Köln
  1. HN1 expression contributes to mitotic fidelity through Aurora A-PLK1-Eg5 axis.
  2. Artificial kinetochore beads establish a biorientation-like state in the spindle.
  3. Ion-mediated condensation controls the mechanics of mitotic chromosomes.
  4. Three-Dimensional Simulation of Whole-Genome Structuring Through the Transition from Anaphase to Interphase.
  5. Recent insights into the causes and consequences of chromosome mis-segregation.
  6. Dynamic phosphorylation of FOXA1 by Aurora B guides post-mitotic gene reactivation.
  7. Aneuploidy of Specific Chromosomes is Beneficial to Cells Lacking Spindle Checkpoint Protein Bub3.
  8. RCC1 depletion drives protein transport defects and rupture in micronuclei.
  9. CtIP regulates G2/M transition and bipolar spindle assembly during mouse oocyte meiosis.
  1. Cytoskeleton (Hoboken). 2024 Sep 18.
    HN1 expression contributes to mitotic fidelity through Aurora A-PLK1-Eg5 axis.
    Gülseren Özduman, Faruk Şimşek, Aadil Javed, Kemal Sami Korkmaz.
      Hematological and neurological expressed 1 (HN1) is homolog of Jupiter protein from Drosophila melanogaster where it functions as a microtubule-associated protein. However, in mammalian cells, HN1 is associated partially with y-tubulin in centrosomes, Stathmin for stabilizing microtubules, and Cdh1 for regulating Cyclin B1 for cell cycle regulation. Moreover, HN1 overexpression leads to early mitotic exit as well. Other molecular functions and interactions of HN1 are not clear yet. Here, based on our previous analysis where HN1 was shown to cluster supernumerary centrosomes and maintain mitotic spindle assembly, we further investigated the role of HN1 in centrosome maintenance and mitotic fidelity in PC-3 prostate and MDA-MB231 mammary cancer cell lines. The maturation-associated roles of HN1 during cell division by examining the AuroraA-PLK1 axis involving a plus end kinesin, Eg5 as well as pericentriolar matrix protein (PCM1) as components of centrosomes were established. We found that HN1 co-localized to centrioles with Eg5 and Aurora A to suppress aberrant spindle formation to ensure the fidelity of centriole/centrosome duplication when overexpressed. Consistently, depleting the HN1 expression using siRNA or shRNA resulted in an increased number of dysregulated mitotic spindle structures, where Aurora A as well as PLK1 co-localizations with Eg5 and PCM1 were disrupted. Further, the PLK1 and Aurora A kinase's phosphorylations also decreased, confirming the hypothesis that the cells struggle in mitotic progression, display nuclear and cytokinetic abnormalities with supernumerary but immature mononucleated centrosomes. In summary, we described the role of HN1 in centrosome nucleation/maturation in PLK1-Eg5 axis and concomitant mitotic spindle formation in human cells.
    Keywords:  Aurora a; Eg5 kinesin; HN1; PLK1; cell cycle
    DOI:  https://doi.org/10.1002/cm.21928
  2. Science. 2024 Sep 20. 385(6715): 1366-1375
    Artificial kinetochore beads establish a biorientation-like state in the spindle.
    Kohei Asai, Yuanzhuo Zhou, Osamu Takenouchi, Tomoya S Kitajima.
      Faithful chromosome segregation requires biorientation, where the pair of kinetochores on the chromosome establish bipolar microtubule attachment. The integrity of the kinetochore, a macromolecular complex built on centromeric DNA, is required for biorientation, but components sufficient for biorientation remain unknown. Here, we show that tethering the outer kinetochore heterodimer NDC80-NUF2 to the surface of apolar microbeads establishes their biorientation-like state in mouse cells. NDC80-NUF2 microbeads align at the spindle equator and self-correct alignment errors. The alignment is associated with stable bipolar microtubule attachment and is independent of the outer kinetochore proteins SPC24-SPC25, KNL1, the Mis12 complex, inner kinetochore proteins, and Aurora. Larger microbeads align more rapidly, suggesting a size-dependent biorientation mechanism. This study demonstrates a biohybrid kinetochore design for synthetic biorientation of microscale particles in cells.
    DOI:  https://doi.org/10.1126/science.adn5428
  3. Nat Mater. 2024 Sep 16.
    Ion-mediated condensation controls the mechanics of mitotic chromosomes.
    Hannes Witt, Janni Harju, Emma M J Chameau, Charlotte M A Bruinsma, Tinka V M Clement, Christian F Nielsen, Ian D Hickson, Erwin J G Peterman, Chase P Broedersz, Gijs J L Wuite.
      During mitosis in eukaryotic cells, mechanical forces generated by the mitotic spindle pull the sister chromatids into the nascent daughter cells. How do mitotic chromosomes achieve the necessary mechanical stiffness and stability to maintain their integrity under these forces? Here we use optical tweezers to show that ions involved in physiological chromosome condensation are crucial for chromosomal stability, stiffness and viscous dissipation. We combine these experiments with high-salt histone depletion and theory to show that chromosomal elasticity originates from the chromatin fibre behaving as a flexible polymer, whereas energy dissipation can be explained by modelling chromatin loops as an entangled polymer solution. Taken together, we show how collective properties of mitotic chromosomes, a biomaterial of incredible complexity, emerge from molecular properties, and how they are controlled by the physico-chemical environment.
    DOI:  https://doi.org/10.1038/s41563-024-01975-0
  4. Methods Mol Biol. 2025 ;2856 293-308
    Three-Dimensional Simulation of Whole-Genome Structuring Through the Transition from Anaphase to Interphase.
    Shin Fujishiro, Masaki Sasai.
      In order to analyze the three-dimensional genome architecture, it is important to simulate how the genome is structured through the cell cycle progression. In this chapter, we present the usage of our computation codes for simulating how the human genome is formed as the cell transforms from anaphase to interphase. We do not use the global Hi-C data as an input into the genome simulation but represent all chromosomes as linear polymers annotated by the neighboring region contact index (NCI), which classifies the A/B type of each local chromatin region. The simulated mitotic chromosomes heterogeneously expand upon entry to the G1 phase, which induces phase separation of A and B chromatin regions, establishing chromosome territories, compartments, and lamina and nucleolus associations in the interphase nucleus. When the appropriate one-dimensional chromosomal annotation is possible, using the protocol of this chapter, one can quantitatively simulate the three-dimensional genome structure and dynamics of human cells of interest.
    Keywords:  Cell cycle; Genome organization; Phase separation; Simulation
    DOI:  https://doi.org/10.1007/978-1-0716-4136-1_18
  5. Oncogene. 2024 Sep 15.
    Recent insights into the causes and consequences of chromosome mis-segregation.
    Romain Devillers, Alexsandro Dos Santos, Quentin Destombes, Mathieu Laplante, Sabine Elowe.
      Mitotic cells face the challenging task of ensuring accurate and equal segregation of their duplicated, condensed chromosomes between the nascent daughter cells. Errors in the process result in chromosome missegregation, a significant consequence of which is the emergence of aneuploidy-characterized by an imbalance in chromosome number-and the associated phenomenon of chromosome instability (CIN). Aneuploidy and CIN are common features of cancer, which leverages them to promote genome heterogeneity and plasticity, thereby facilitating rapid tumor evolution. Recent research has provided insights into how mitotic errors shape cancer genomes by inducing both numerical and structural chromosomal changes that drive tumor initiation and progression. In this review, we survey recent findings regarding the mitotic causes and consequences of aneuploidy. We discuss new findings into the types of chromosome segregation errors that lead to aneuploidy and novel pathways that protect genome integrity during mitosis. Finally, we describe new developments in our understanding of the immediate consequences of chromosome mis-segregation on the genome stability of daughter cells.
    DOI:  https://doi.org/10.1038/s41388-024-03163-5
  6. Cell Rep. 2024 Sep 13. pii: S2211-1247(24)01090-8. [Epub ahead of print]43(9): 114739
    Dynamic phosphorylation of FOXA1 by Aurora B guides post-mitotic gene reactivation.
    Ting Zhang, Shuaiyu Liu, Olanrewaju Durojaye, Fangyuan Xiong, Zhiyou Fang, Tahir Ullah, Chuanhai Fu, Bo Sun, Hao Jiang, Peng Xia, Zhikai Wang, Xuebiao Yao, Xing Liu.
      FOXA1 serves as a crucial pioneer transcription factor during developmental processes and plays a pivotal role as a mitotic bookmarking factor to perpetuate gene expression profiles and maintain cellular identity. During mitosis, the majority of FOXA1 dissociates from specific DNA binding sites and redistributes to non-specific binding sites; however, the regulatory mechanisms governing molecular dynamics and activity of FOXA1 remain elusive. Here, we show that mitotic kinase Aurora B specifies the different DNA binding modes of FOXA1 and guides FOXA1 biomolecular condensation in mitosis. Mechanistically, Aurora B kinase phosphorylates FOXA1 at Serine 221 (S221) to liberate the specific, but not the non-specific, DNA binding. Interestingly, the phosphorylation of S221 attenuates the FOXA1 condensation that requires specific DNA binding. Importantly, perturbation of the dynamic phosphorylation impairs accurate gene reactivation and cell proliferation, suggesting that reversible mitotic protein phosphorylation emerges as a fundamental mechanism for the spatiotemporal control of mitotic bookmarking.
    Keywords:  Aurora B; CP: Cell biology; FOXA1; biomolecular condensation; bookmarking factor; gene reactivation; mitosis; phosphorylation
    DOI:  https://doi.org/10.1016/j.celrep.2024.114739
  7. bioRxiv. 2024 Sep 03. pii: 2024.09.02.610809. [Epub ahead of print]
    Aneuploidy of Specific Chromosomes is Beneficial to Cells Lacking Spindle Checkpoint Protein Bub3.
    Pallavi Gadgil, Olivia Ballew, Timothy J Sullivan, Soni Lacefield.
      Aneuploidy typically poses challenges for cell survival and growth. However, recent studies have identified exceptions where aneuploidy is beneficial for cells with mutations in certain regulatory genes. Our research reveals that cells lacking the spindle checkpoint gene BUB3 exhibit aneuploidy of select chromosomes. While the spindle checkpoint is not essential in budding yeast, the loss of BUB3 and BUB1 increases the probability of chromosome missegregation compared to wildtype cells. Contrary to the prevailing assumption that the aneuploid cells would be outcompeted due to growth defects, our findings demonstrate that bub3 Δ cells consistently maintained aneuploidy of specific chromosomes over many generations. We investigated whether the persistence of these additional chromosomes in bub3 Δ cells resulted from the beneficial elevated expression of certain genes, or mere tolerance. We identified several genes involved in chromosome segregation and cell cycle regulation that confer an advantage to Bub3-depleted cells. Overall, our results suggest that the upregulation of specific genes through aneuploidy may provide a survival and growth advantage to strains with poor chromosome segregation fidelity.
    AUTHOR SUMMARY: Accurate chromosome segregation is crucial for the proper development of all living organisms. Errors in chromosome segregation can lead to aneuploidy, characterized by an abnormal number of chromosomes, which generally impairs cell survival and growth. However, under certain stress conditions, such as in various cancers, cells with specific mutations and extra copies of advantageous chromosomes exhibit improved survival and proliferation. In our study, we discovered that cells lacking the spindle checkpoint protein Bub3 became aneuploid, retaining specific chromosomes. This finding was unexpected because although bub3 Δ cells have a higher rate of chromosome mis-segregation, they were not thought to maintain an aneuploid karyotype. We investigated whether the increased copy number of specific genes on these acquired chromosomes offered a benefit to Bub3-deficient cells. Our results revealed that several genes involved in chromosome segregation and cell cycle regulation prevented the gain of chromosomes upon Bub3-depletion, suggesting that these genes confer a survival advantage. Overall, our study demonstrates that cells lacking Bub3 selectively retain specific chromosomes to increase the copy number of genes that promote proper chromosome segregation.
    DOI:  https://doi.org/10.1101/2024.09.02.610809
  8. bioRxiv. 2024 Sep 05. pii: 2024.09.04.611299. [Epub ahead of print]
    RCC1 depletion drives protein transport defects and rupture in micronuclei.
    Molly G Zych, Maya Contreras, Manasvita Vashisth, Anna E Mammel, Gavin Ha, Emily M Hatch.
      Micronuclei (MN) are a commonly used marker of chromosome instability that form when missegregated chromatin recruits its own nuclear envelope (NE) after mitosis. MN frequently rupture, which results in genome instability, upregulation of metastatic genes, and increased immune signaling. MN rupture is linked to NE defects, but the cause of these defects is poorly understood. Previous work from our lab found that chromosome identity correlates with rupture timing for small MN, i.e. MN containing a short chromosome, with more euchromatic chromosomes forming more stable MN with fewer nuclear lamina gaps. Here we demonstrate that histone methylation promotes rupture and nuclear lamina defects in small MN. This correlates with increased MN size, and we go on to find that all MN have a constitutive nuclear export defect that drives MN growth and nuclear lamina gap expansion, making the MN susceptible to rupture. We demonstrate that these export defects arise from decreased RCC1 levels in MN and that additional loss of RCC1 caused by low histone methylation in small euchromatic MN results in additional import defects that suppress nuclear lamina gaps and MN rupture. Through analysis of mutational signatures associated with early and late rupturing chromosomes in the Pan-Cancer Analysis of Whole Genomes (PCAWG) dataset, we identify an enrichment of APOBEC and DNA polymerase E hypermutation signatures in chromothripsis events on early and mid rupturing chromosomes, respectively, suggesting that MN rupture timing could determine the landscape of structural variation in chromothripsis. Our study defines a new model of MN rupture where increased MN growth, caused by defects in protein export, drives gaps in nuclear lamina organization that make the MN susceptible to membrane rupture with long-lasting effects on genome architecture.
    DOI:  https://doi.org/10.1101/2024.09.04.611299
  9. J Genet Genomics. 2024 Sep 12. pii: S1673-8527(24)00242-X. [Epub ahead of print]
    CtIP regulates G2/M transition and bipolar spindle assembly during mouse oocyte meiosis.
    Wei Yue, Hong-Yong Zhang, Heide Schatten, Tie-Gang Meng, Qing-Yuan Sun.
      CtBP-interacting protein (CtIP) is known for its multifaceted roles in DNA repair and genomic stability, directing the homologous recombination-mediated DNA double-stranded break (DSBs) repair pathway via DNA end resection, an essential error-free repair process vital for genome stability. Mammalian oocytes are highly prone to DNA damage accumulation due to prolonged G2/prophase arrest. Here, we explore the functions of CtIP in meiotic cell cycle regulation via a mouse oocyte model. Depletion of CtIP by siRNA injection results in delayed germinal vesicle breakdown and failed polar body extrusion. Mechanistically, CtIP deficiency increases DNA damage and decreases the expression and nuclear entry of CCNB1, resulting in marked impairment of meiotic resumption, which can be rescued by exogenous CCNB1 overexpression. Furthermore, depletion of CtIP disrupts MTOCs coalescence at spindle poles as indicated by failed accumulation of γ-tubulin, p-Aurora kinase A, Kif2A, and TPX2, leading to abnormal spindle assembly and prometaphase arrest. These results provide valuable insights into the important roles of CtIP in the G2/M checkpoint and spindle assembly in mouse oocyte meiotic cell cycle regulation.
    Keywords:  CtIP; G2/M transition; Meiosis; Oocyte; Spindle assembly
    DOI:  https://doi.org/10.1016/j.jgg.2024.09.005
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