bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2024‒05‒26
twenty-one papers selected by
Valentina Piano, Uniklinik Köln
  1. TIP60 acetylation of Bub1 regulates centromeric H2AT120 phosphorylation for faithful chromosome segregation.
  2. Microtubule end-on attachment maturation regulates Mps1 association with its kinetochore receptor.
  3. A conserved site on Ndc80 complex facilitates dynamic recruitment of Mps1 to yeast kinetochores to promote accurate chromosome segregation.
  4. Contribution of CENP-F to FOXM1-Mediated Discordant Centromere and Kinetochore Transcriptional Regulation.
  5. A communication hub for phosphoregulation of kinetochore-microtubule attachment.
  6. Bipartite binding interface recruiting HP1 to chromosomal passenger complex at inner centromeres.
  7. Microtubule reorganization during mitotic cell division in the dinoflagellate Ostreospis cf. ovata.
  8. Cryptococcus neoformans Slu7 ensures nuclear positioning during mitotic progression through RNA splicing.
  9. The C-terminal disordered loop domain of Apc8 unlocks APC/C mitotic activation.
  10. The tragedy of mitotic catastrophe in podocytes.
  11. Deep radial basis function networks with subcategorization for mitosis detection in breast histopathology images.
  12. Life-cycle-coupled evolution of mitosis in close relatives of animals.
  13. FBXO42 activity is required to prevent mitotic arrest, spindle assembly checkpoint activation and lethality in glioblastoma and other cancers.
  14. Nitrogen availability is important for preventing catastrophic mitosis in fission yeast.
  15. Cell Competition Eliminates Aneuploid Human Pluripotent Stem Cells.
  16. In-cell chemical construction of a photoswitchable CENP-E using a photochromic covalent inhibitor.
  17. Toward interpretable and generalized mitosis detection in digital pathology using deep learning.
  18. Mammalian RNAi represses pericentromeric lncRNAs to maintain genome stability.
  19. Crosstalk between mitotic reassembly and repair of the nuclear envelope.
  20. Small spaces, big problems: The abnormal nucleoplasm of micronuclei and its consequences.
  21. SKA3 Expression as a Prognostic Factor for Patients with Pancreatic Adenocarcinoma.
  1. Sci China Life Sci. 2024 May 17.
    TIP60 acetylation of Bub1 regulates centromeric H2AT120 phosphorylation for faithful chromosome segregation.
    Mengjie Sun, Biying Yang, Guangwei Xin, Yao Wang, Jia Luo, Qing Jiang, Chuanmao Zhang.
      Proper function of the centromeres ensures correct attachment of kinetochores to spindle microtubules and faithful chromosome segregation in mitosis. Defects in the integrity and function of centromeres can result in chromosome missegregation and genomic instability. Bub1 is essential for the mitotic centromere dynamics, yet the underlying molecular mechanisms remain largely unclear. Here, we demonstrate that TIP60 acetylates Bub1 at K424 and K431 on kinetochores in early mitosis. This acetylation increases the kinase activity of Bub1 to phosphorylate centromeric histone H2A at T120 (H2ApT120), which recruits Aurora B and Shugoshin 1 (Sgo1) to regulate centromere integrity, protect centromeric cohesion, and ensure the subsequent faithful chromosome segregation. Expression of the non-acetylated Bub1 mutant reduces its kinase activity, decreases the level of H2ApT120, and disrupts the recruitment of centromere proteins and chromosome congression, leading to genomic instability of daughter cells. When cells exit mitosis, HDAC1-regulated deacetylation of Bub1 decreases H2ApT120 levels and thereby promotes the departure of centromeric CPC and Sgo1, ensuring timely centromeres disassembly. Collectively, our results reveal a molecular mechanism by which the acetylation and deacetylation cycle of Bub1 modulates the phosphorylation of H2A at T120 for recruitment of Aurora B and Sgo1 to the centromeres, ensuring faithful chromosome segregation during mitosis.
    Keywords:  Bub1; H2ApT120; TIP60; acetylation; chromosome segregation
    DOI:  https://doi.org/10.1007/s11427-023-2604-8
  2. Curr Biol. 2024 May 16. pii: S0960-9822(24)00402-0. [Epub ahead of print]
    Microtubule end-on attachment maturation regulates Mps1 association with its kinetochore receptor.
    Richard Pleuger, Christian Cozma, Simone Hohoff, Christian Denkhaus, Alexander Dudziak, Farnusch Kaschani, Markus Kaiser, Andrea Musacchio, Ingrid R Vetter, Stefan Westermann.
      Faithful chromosome segregation requires that sister chromatids establish bi-oriented kinetochore-microtubule attachments. The spindle assembly checkpoint (SAC) prevents premature anaphase onset with incomplete attachments. However, how microtubule attachment and checkpoint signaling are coordinated remains unclear. The conserved kinase Mps1 initiates SAC signaling by localizing transiently to kinetochores in prometaphase and is released upon bi-orientation. Using biochemistry, structure predictions, and cellular assays, we shed light on this dynamic behavior in Saccharomyces cerevisiae. A conserved N-terminal segment of Mps1 binds the neck region of Ndc80:Nuf2, the main microtubule receptor of kinetochores. Mutational disruption of this interface, located at the backside of the paired CH domains and opposite the microtubule-binding site, prevents Mps1 localization, eliminates SAC signaling, and impairs growth. The same interface of Ndc80:Nuf2 binds the microtubule-associated Dam1 complex. We demonstrate that the error correction kinase Ipl1/Aurora B controls the competition between Dam1 and Mps1 for the same binding site. Thus, binding of the Dam1 complex to Ndc80:Nuf2 may release Mps1 from the kinetochore to promote anaphase onset.
    Keywords:  cell cycle; chromosome bi-orientation; chromosome segregation; error correction; mitosis; spindle assembly checkpoint; tension
    DOI:  https://doi.org/10.1016/j.cub.2024.03.062
  3. Curr Biol. 2024 May 16. pii: S0960-9822(24)00528-1. [Epub ahead of print]
    A conserved site on Ndc80 complex facilitates dynamic recruitment of Mps1 to yeast kinetochores to promote accurate chromosome segregation.
    Emily J Parnell, Erin E Jenson, Matthew P Miller.
      Accurate chromosome segregation relies on kinetochores carrying out multiple functions, including establishing and maintaining microtubule attachments, forming precise bi-oriented attachments between sister chromatids, and activating the spindle assembly checkpoint. Central to these processes is the highly conserved Ndc80 complex. This kinetochore subcomplex interacts directly with microtubules but also serves as a critical platform for recruiting kinetochore-associated factors and as a key substrate for error correction kinases. The precise manner in which these kinetochore factors interact and regulate each other's function remains unknown, considerably hindering our understanding of how Ndc80 complex-dependent processes function together to orchestrate accurate chromosome segregation. Here, we aimed to uncover the role of Nuf2's CH domain, a component of the Ndc80 complex, in ensuring these processes. Through extensive mutational analysis, we identified a conserved interaction domain composed of two segments in Nuf2's CH domain that form the binding site for Mps1 within the yeast Ndc80 complex. Interestingly, this site also associates with the Dam1 complex, suggesting Mps1 recruitment may be subject to regulation by competitive binding with other factors. Mutants disrupting this "interaction hub" exhibit defects in spindle assembly checkpoint function and severe chromosome segregation errors. Significantly, specifically restoring Mps1-Ndc80 complex association rescues these defects. Our findings shed light on the intricate regulation of Ndc80 complex-dependent functions and highlight the essential role of Mps1 in kinetochore bi-orientation and accurate chromosome segregation.
    Keywords:  Dam1 complex; Mps1; Ndc80 complex; Nuf2; SAC; bi-orientation; chromosome segregation; kinetochore; spindle assembly checkpoint
    DOI:  https://doi.org/10.1016/j.cub.2024.04.054
  4. Mol Cell Biol. 2024 May 23. 1-17
    Contribution of CENP-F to FOXM1-Mediated Discordant Centromere and Kinetochore Transcriptional Regulation.
    Sakshi Khurana, Dileep Varma, Daniel R Foltz.
      Proper chromosome segregation is required to ensure chromosomal stability. The centromere (CEN) is a unique chromatin domain defined by CENP-A and is responsible for recruiting the kinetochore (KT) during mitosis, ultimately regulating microtubule spindle attachment and mitotic checkpoint function. Upregulation of many CEN/KT genes is commonly observed in cancer. Here, we show that although FOXM1 occupies promoters of many CEN/KT genes with MYBL2, FOXM1 overexpression alone is insufficient to drive the FOXM1-correlated transcriptional program. CENP-F is canonically an outer kinetochore component; however, it functions with FOXM1 to coregulate G2/M transcription and proper chromosome segregation. Loss of CENP-F results in altered chromatin accessibility at G2/M genes and reduced FOXM1-MBB complex formation. We show that coordinated CENP-FFOXM1 transcriptional regulation is a cancer-specific function. We observe a small subset of CEN/KT genes including CENP-C, that are not regulated by FOXM1. Upregulation of CENP-C in the context of CENP-A overexpression leads to increased chromosome missegregation and cell death suggesting that escape of CENP-C from FOXM1 regulation is a cancer survival mechanism. Together, we show that FOXM1 and CENP-F coordinately regulate G2/M genes, and this coordination is specific to a subset of genes to allow for maintenance of chromosome instability levels and subsequent cell survival.
    Keywords:  Centromere; cell cycle; chromosome segregation; kinetochore; transcriptional regulation
    DOI:  https://doi.org/10.1080/10985549.2024.2350543
  5. Curr Biol. 2024 May 16. pii: S0960-9822(24)00580-3. [Epub ahead of print]
    A communication hub for phosphoregulation of kinetochore-microtubule attachment.
    Jacob A Zahm, Stephen C Harrison.
      The Mps1 and Aurora B kinases regulate and monitor kinetochore attachment to spindle microtubules during cell division, ultimately ensuring accurate chromosome segregation. In yeast, the critical spindle attachment components are the Ndc80 and Dam1 complexes (Ndc80c and DASH/Dam1c, respectively). Ndc80c is a 600-Å-long heterotetramer that binds microtubules through a globular "head" at one end and centromere-proximal kinetochore components through a globular knob at the other end. Dam1c is a heterodecamer that forms a ring of 16-17 protomers around the shaft of the single kinetochore microtubule in point-centromere yeast. The ring coordinates the approximately eight Ndc80c rods per kinetochore. In published work, we showed that a site on the globular "head" of Ndc80c, including residues from both Ndc80 and Nuf2, binds a bipartite segment in the long C-terminal extension of Dam1. Results reported here show, both by in vitro binding experiments and by crystal structure determination, that the same site binds a conserved segment in the long N-terminal extension of Mps1. It also binds, less tightly, a conserved segment in the N-terminal extension of Ipl1 (yeast Aurora B). Together with results from experiments in yeast cells and from biochemical assays reported in two accompanying papers, the structures and graded affinities identify a communication hub for ensuring uniform bipolar attachment and for signaling anaphase onset.
    Keywords:  Aurora B; Mps1; X-ray crystallography; error correction; kinetochore; mitosis; point-centromere yeast; spindle-assembly checkpoint
    DOI:  https://doi.org/10.1016/j.cub.2024.04.067
  6. J Cell Biol. 2024 Sep 02. pii: e202312021. [Epub ahead of print]223(9):
    Bipartite binding interface recruiting HP1 to chromosomal passenger complex at inner centromeres.
    Kosuke Sako, Ayako Furukawa, Ryu-Suke Nozawa, Jun-Ichi Kurita, Yoshifumi Nishimura, Toru Hirota.
      Maintenance of ploidy depends on the mitotic kinase Aurora B, the catalytic subunit of the chromosomal passenger complex (CPC) whose proficient activity is supported by HP1 enriched at inner centromeres. HP1 is known to associate with INCENP of the CPC in a manner that depends on the PVI motif conserved across HP1 interactors. Here, we found that the interaction of INCENP with HP1 requires not only the PVI motif but also its C-terminally juxtaposed domain. Remarkably, these domains conditionally fold the β-strand (PVI motif) and the α-helix from a disordered sequence upon HP1 binding and render INCENP with high affinity to HP1. This bipartite binding domain termed SSH domain (Structure composed of Strand and Helix) is necessary and sufficient to attain a predominant interaction of HP1 with INCENP. These results identify a unique HP1-binding module in INCENP that ensures enrichment of HP1 at inner centromeres, Aurora B activity, and thereby mitotic fidelity.
    DOI:  https://doi.org/10.1083/jcb.202312021
  7. J Cell Sci. 2024 May 21. pii: jcs.261733. [Epub ahead of print]
    Microtubule reorganization during mitotic cell division in the dinoflagellate Ostreospis cf. ovata.
    David Velasquez-Carvajal, Flavie Garampon, L Besnardeau, Rodolphe Lemée, Sebastian Schaub, Stefania Castagnetti.
      Dinoflagellates are marine organisms that undergo seasonal proliferation events known as algal blooms. Vegetative cell proliferation is a main contributing factor in these events. However, mechanistical understanding of mitosis and cytokinesis in dinoflagellate remains rudimentary. Using an optimized immunofluorescence protocol, we analysed changes in microtubule organization occurring during the mitotic cycle of the toxic dinoflagellate Ostreopsis cf. ovata. We find that the two flagella and the cortical microtubule array persist throughout the mitotic cycle. Two cytoplasmic microtubule bundles originate from the ventral area, where the basal bodies are located: a cortical bundle and a cytoplasmic bundle. The latter associates with the nucleus in the cell centre before mitosis and with the acentrosomal extranuclear spindle during mitosis. Analysis of tubulin post-translational modifications identifies two populations of spindle microtubules: polar acetylated microtubules whose length is constant and central tyrosinated microtubules which elongate during chromosome segregation. During cell division a microtubule rich structure forms along the dorsal-ventral axis, associated with the site of cytokinesis, consistent with a cytokinetic mechanism independent of the actomyosin ring typical of animal and yeast cells.
    Keywords:  Centrin; Cytokinesis; Dinoflagellates; Microtubules; Mitosis
    DOI:  https://doi.org/10.1242/jcs.261733
  8. PLoS Genet. 2024 May 20. 20(5): e1011272
    Cryptococcus neoformans Slu7 ensures nuclear positioning during mitotic progression through RNA splicing.
    Vishnu Priya Krishnan, Manendra Singh Negi, Raghavaram Peesapati, Usha Vijayraghavan.
      The position of the nucleus before it divides during mitosis is variable in different budding yeasts. Studies in the pathogenic intron-rich fungus Cryptococcus neoformans reveal that the nucleus moves entirely into the daughter bud before its division. Here, we report functions of a zinc finger motif containing spliceosome protein C. neoformans Slu7 (CnSlu7) in cell cycle progression. The budding yeast and fission yeast homologs of Slu7 have predominant roles for intron 3' splice site definition during pre-mRNA splicing. Using a conditional knockdown strategy, we show CnSlu7 is an essential factor for viability and is required for efficient cell cycle progression with major role during mitosis. Aberrant nuclear migration, including improper positioning of the nucleus as well as the spindle, were frequently observed in cells depleted of CnSlu7. However, cell cycle delays observed due to Slu7 depletion did not activate the Mad2-dependent spindle assembly checkpoint (SAC). Mining of the global transcriptome changes in the Slu7 knockdown strain identified downregulation of transcripts encoding several cell cycle regulators and cytoskeletal factors for nuclear migration, and the splicing of specific introns of these genes was CnSlu7 dependent. To test the importance of splicing activity of CnSlu7 on nuclear migration, we complemented Slu7 knockdown cells with an intron less PAC1 minigene and demonstrated that the nuclear migration defects were significantly rescued. These findings show that CnSlu7 regulates the functions of diverse cell cycle regulators and cytoskeletal components, ensuring timely cell cycle transitions and nuclear division during mitosis.
    DOI:  https://doi.org/10.1371/journal.pgen.1011272
  9. Cell Rep. 2024 May 21. pii: S2211-1247(24)00590-4. [Epub ahead of print]43(6): 114262
    The C-terminal disordered loop domain of Apc8 unlocks APC/C mitotic activation.
    Sarah Darling, Kazuyuki Fujimitsu, Kim Hou Chia, Juan Zou, Juri Rappsilber, Hiroyuki Yamano.
      The anaphase-promoting complex/cyclosome (APC/C) is a critical and tightly regulated E3 ligase that orchestrates the cellular life cycle by controlling the degradation of cell cycle regulators. An intriguing feature of this complex is an autoinhibition mechanism: an intrinsically disordered loop domain, Apc1-300L, blocks Cdc20 coactivator binding, yet phosphorylation of Apc1-300L counteracts this autoinhibition. Many such disordered loops within APC/C remain unexplored. Our systematic analysis of loop-deficient APC/C mutants uncovered a pivotal role for Apc8's C-terminal loop (Apc8-L) in mitotic activation. Apc8-L directly recruits the CDK adaptor protein, Xe-p9/Cks2, positioning the Xe-p9-CDK-CycB complex near Apc1-300L. This stimulates the phosphorylation and removal of Apc1-300L, prompting the formation of active APC/CCdc20. Strikingly, without both Apc8-L and Apc3-L, the APC/C is rendered inactive during mitosis, highlighting Apc8-L's synergistic role with other loops and kinases. This study broadens our understanding of the intricate dynamics in APC/C regulation and provides insights on the regulation of macromolecular complexes.
    Keywords:  APC/C; CDK; CP: Molecular biology; Cdc20; Cks; cell cycle; crosslinking mass spectrometry; intrinsically disordered regions; phosphorylation; proteolysis; ubiquitin ligase
    DOI:  https://doi.org/10.1016/j.celrep.2024.114262
  10. Kidney Int. 2024 Jun;pii: S0085-2538(24)00071-1. [Epub ahead of print]105(6): 1153-1156
    The tragedy of mitotic catastrophe in podocytes.
    Stuart J Shankland, Behzad Najafian, Oliver Wessely.
      
    Keywords:  cell cycle; glomerulus; kidney; mitosis; podocyte; polyploidy
    DOI:  https://doi.org/10.1016/j.kint.2024.01.015
  11. Med Image Anal. 2024 May 15. pii: S1361-8415(24)00129-4. [Epub ahead of print]95 103204
    Deep radial basis function networks with subcategorization for mitosis detection in breast histopathology images.
    Qiling Tang, Yu Cai.
      Due to the intra-class diversity of mitotic cells and the morphological overlap with similarly looking imposters, automatic mitosis detection in histopathology slides is still a challenging task. In this paper, we propose a novel mitosis detection model in a weakly supervised way, which consists of a candidate proposal network and a verification network. The candidate proposal network based on patch learning aims to separate both mitotic cells and their mimics from the background as candidate objects, which substantially reduces missed detections in the screening process of candidates. These obtained candidate results are then fed into the verification network for mitosis refinement. The verification network adopts an RBF-based subcategorization scheme to deal with the problems of high intra-class variability of mitosis and the mimics with similar appearance. We utilize the RBF centers to define subcategories containing mitotic cells with similar properties and capture representative RBF center locations through joint training of classification and clustering. Due to the lower intra-class variation within a subcategory, the localized feature space at subcategory level can better characterize a certain type of mitotic figures and can provide a better similarity measurement for distinguishing mitotic cells from nonmitotic cells. Our experiments manifest that this subcategorization scheme helps improve the performance of mitosis detection and achieves state-of-the-art results on the publicly available mitosis datasets using only weak labels.
    Keywords:  Deep clustering; Mitosis detection; Radial basis function; Subcategorization; Weak supervision
    DOI:  https://doi.org/10.1016/j.media.2024.103204
  12. Nature. 2024 May 22.
    Life-cycle-coupled evolution of mitosis in close relatives of animals.
    Hiral Shah, Marine Olivetta, Chandni Bhickta, Paolo Ronchi, Monika Trupinić, Eelco C Tromer, Iva M Tolić, Yannick Schwab, Omaya Dudin, Gautam Dey.
      Eukaryotes have evolved towards one of two extremes along a spectrum of strategies for remodelling the nuclear envelope during cell division: disassembling the nuclear envelope in an open mitosis or constructing an intranuclear spindle in a closed mitosis1,2. Both classes of mitotic remodelling involve key differences in the core division machinery but the evolutionary reasons for adopting a specific mechanism are unclear. Here we use an integrated comparative genomics and ultrastructural imaging approach to investigate mitotic strategies in Ichthyosporea, close relatives of animals and fungi. We show that species in this clade have diverged towards either a fungal-like closed mitosis or an animal-like open mitosis, probably to support distinct multinucleated or uninucleated states. Our results indicate that multinucleated life cycles favour the evolution of closed mitosis.
    DOI:  https://doi.org/10.1038/s41586-024-07430-z
  13. NAR Cancer. 2024 Jun;6(2): zcae021
    FBXO42 activity is required to prevent mitotic arrest, spindle assembly checkpoint activation and lethality in glioblastoma and other cancers.
    Pia Hoellerbauer, Megan Kufeld, Sonali Arora, Kelly Mitchell, Emily J Girard, Jacob A Herman, James M Olson, Patrick J Paddison.
      Glioblastoma (GBM) is the most common and aggressive brain tumor in adults. To identify genes differentially required for the viability of GBM stem-like cells (GSCs), we performed functional genomic lethality screens comparing GSCs and control human neural stem cells. Among top-scoring hits in a subset of GBM cells was the F-box-containing gene FBXO42, which was also predicted to be essential in ∼15% of cell lines derived from a broad range of cancers. Mechanistic studies revealed that, in sensitive cells, FBXO42 activity prevents chromosome alignment defects, mitotic cell cycle arrest and cell death. The cell cycle arrest, but not the cell death, triggered by FBXO42 inactivation could be suppressed by brief exposure to a chemical inhibitor of Mps1, a key spindle assembly checkpoint (SAC) kinase. FBXO42's cancer-essential function requires its F-box and Kelch domains, which are necessary for FBXO42's substrate recognition and targeting by SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex. However, none of FBXO42's previously proposed targets, including ING4, p53 and RBPJ, were responsible for the observed phenotypes. Instead, our results suggest that FBOX42 alters the activity of one or more proteins that perturb chromosome-microtubule dynamics in cancer cells, which in turn leads to induction of the SAC and cell death.
    DOI:  https://doi.org/10.1093/narcan/zcae021
  14. J Cell Sci. 2024 May 23. pii: jcs.262196. [Epub ahead of print]
    Nitrogen availability is important for preventing catastrophic mitosis in fission yeast.
    Viacheslav Zemlianski, Anna Marešová, Jarmila Princová, Roman Holič, Robert Häsler, Manuel José Ramos Del Río, Laurane Lhoste, Maryia Zarechyntsava, Martin Převorovský.
      Mitosis is a critical stage in the cell cycle, controlled by a vast network of regulators responding to multiple internal and external factors. The fission yeast Schizosaccharomyces pombe may demonstrate catastrophic mitotic phenotypes due to mutations or drug treatments. One of the factors provoking catastrophic mitosis is a disturbed lipid metabolism, resulting from e.g. mutations in acetyl-CoA/biotin carboxylase (cut6), in fatty acid synthase (fas2/lsd1), or in the transcriptional regulator of lipid metabolism (cbf11) genes, as well as treatment with inhibitors of fatty acid synthesis. It was previously shown that mitotic fidelity in lipid metabolism mutants can be partially rescued by ammonium chloride. In this study we demonstrate that mitotic fidelity can be improved by multiple nitrogen sources. Moreover, this improvement is not limited to lipid metabolism disturbances but also applies to a number of unrelated mitotic mutants. Interestingly, the partial rescue is not achieved by restoring the lipid metabolism state, but rather indirectly. Our results highlight a novel role for nitrogen availability in mitotic fidelity.
    Keywords:  Closed mitosis; Cut; Lipid metabolism; Mitotic catastrophe; Nitrogen availability; TOR
    DOI:  https://doi.org/10.1242/jcs.262196
  15. bioRxiv. 2024 May 10. pii: 2024.05.08.593217. [Epub ahead of print]
    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 a persistently high rate of mitotic errors that cause aneuploidy, or chromosome imbalances. Consequently, to maintain genome stability, aneuploidy must inhibit hPSC proliferation, but the mechanisms are unknown. Here, we surprisingly find that homogeneous aneuploid populations of hPSCs proliferate unlike aneuploid non-transformed somatic cells. Instead, in mosaic populations, cell non-autonomous competition between neighboring diploid and aneuploid hPSCs eliminates less fit aneuploid cells. Aneuploid hPSCs with lower Myc or higher p53 levels relative to diploid neighbors are outcompeted but conversely gain a selective advantage when Myc and p53 relative abundance switches. Thus, although hPSCs frequently missegregate chromosomes and inherently tolerate aneuploidy, Myc- and p53-driven cell competition preserves their genome integrity. These findings have important implications for the use of hPSCs in regenerative medicine and for how diploid human embryos are established despite the prevalence of aneuploidy during early development.
    DOI:  https://doi.org/10.1101/2024.05.08.593217
  16. Org Biomol Chem. 2024 May 24.
    In-cell chemical construction of a photoswitchable CENP-E using a photochromic covalent inhibitor.
    Kazuya Matsuo, Shusuke Yamaoka, Tomonori Waku, Akio Kobori.
      An arylazopyrazole-based covalent inhibitor targeting the mitotic motor protein of centromere-associated protein E (CENP-E) was developed. Using this photoswitchable inhibitor, a photoswitchable CENP-E was chemically constructed in cells, which enabled to local control of mitotic cell division with light illumination.
    DOI:  https://doi.org/10.1039/d4ob00647j
  17. Digit Health. 2024 Jan-Dec;10:10 20552076241255471
    Toward interpretable and generalized mitosis detection in digital pathology using deep learning.
    Hasan Farooq, Saira Saleem, Iffat Aleem, Ayesha Iftikhar, Umer Nisar Sheikh, Hammad Naveed.
      Objective: The mitotic activity index is an important prognostic factor in the diagnosis of cancer. The task of mitosis detection is difficult as the nuclei are microscopic in size and partially labeled, and there are many more non-mitotic nuclei compared to mitotic ones. In this paper, we highlight the challenges of current mitosis detection pipelines and propose a method to tackle these challenges.Methods: Our proposed methodology is inspired from recent research on deep learning and an extensive analysis on the dataset and training pipeline. We first used the MiDoG'22 dataset for training, validation, and testing. We then tested the methodology without fine-tuning on the TUPAC'16 dataset and on a real-time case from Shaukat Khanum Memorial Cancer Hospital and Research Centre.
    Results: Our methodology has shown promising results both quantitatively and qualitatively. Quantitatively, our methodology achieved an F1-score of 0.87 on the MiDoG'22 dataset and an F1-score of 0.83 on the TUPAC dataset. Qualitatively, our methodology is generalizable and interpretable across various datasets and clinical settings.
    Conclusion: In this paper, we highlight the challenges of current mitosis detection pipelines and propose a method that can accurately predict mitotic nuclei. We illustrate the accuracy, generalizability, and interpretability of our approach across various datasets and clinical settings. Our methodology can speed up the adoption of computer-aided digital pathology in clinical settings.
    Keywords:  Mitosis detection; deep learning; digital pathology; generalizability; interpretable AI
    DOI:  https://doi.org/10.1177/20552076241255471
  18. bioRxiv. 2024 May 10. pii: 2024.05.09.593425. [Epub ahead of print]
    Mammalian RNAi represses pericentromeric lncRNAs to maintain genome stability.
    Rafael Sandoval, Corinne N Dilsavor, Nadia R Grishanina, Vandan Patel, Jesse R Zamudio.
      Mammalian pericentromeric tandem repeats produce long noncoding RNAs (lncRNAs) that are dysregulated in cancer and linked to genomic instability. Identifying the basic molecular characteristics of these lncRNAs and their regulation is important to understanding their biological function. Here, we determine that the Argonaute (Ago) proteins of the RNA interference (RNAi) pathway directly and uniformly repress bidirectional pericentromeric lncRNAs in a Dicer-dependent manner in mouse embryonic and adult stem cells. Ago-dependent and Dicer-dependent autoregulatory small RNAs were identified within pericentromeric lncRNA degradation intermediates. We develop an RNase H cleavage assay to determine the relative proportions and lengths of the pericentromeric lncRNA targets. We find that 5'-phosphate and non-polyadenylated bidirectional pericentromeric lncRNAs are expressed at similar proportions. These lncRNAs can span up to 9 repeats, with transcription from the reverse strand template yielding the longer products. Using pericentromeric repeat RNA reporters, we determine that Ago represses pericentromeric lncRNAs after S phase transcription. Upon loss of Ago, pericentromeric lncRNA dysregulation results in delayed cell cycle progression, a defective mitotic spindle assembly checkpoint (SAC) and genomic instability. These results show that an evolutionarily conserved Ago activity at pericentromeres contributes to mammalian genome stability.
    DOI:  https://doi.org/10.1101/2024.05.09.593425
  19. Nucleus. 2024 Dec;15(1): 2352203
    Crosstalk between mitotic reassembly and repair of the nuclear envelope.
    Yohei Kono, Takeshi Shimi.
      In eukaryotic cells, the nuclear envelope (NE) is a membrane partition between the nucleus and the cytoplasm to compartmentalize nuclear contents. It plays an important role in facilitating nuclear functions including transcription, DNA replication and repair. In mammalian cells, the NE breaks down and then reforms during cell division, and in interphase it is restored shortly after the NE rupture induced by mechanical force. In this way, the partitioning effect is regulated through dynamic processes throughout the cell cycle. A failure in rebuilding the NE structure triggers the mixing of nuclear and cytoplasmic contents, leading to catastrophic consequences for the nuclear functions. Whereas the precise details of molecular mechanisms for NE reformation during cell division and NE restoration in interphase are still being investigated, here, we mostly focus on mammalian cells to describe key aspects that have been identified and to discuss the crosstalk between them.
    Keywords:  BAF; ESCRT-III; NPC; lamin; lamina; nuclear envelope; nuclear envelope reassembly; nuclear envelope rupture
    DOI:  https://doi.org/10.1080/19491034.2024.2352203
  20. Curr Opin Struct Biol. 2024 May 18. pii: S0959-440X(24)00066-6. [Epub ahead of print]87 102839
    Small spaces, big problems: The abnormal nucleoplasm of micronuclei and its consequences.
    Molly G Zych, Emily M Hatch.
      Micronuclei (MN) form from missegregated chromatin that recruits its own nuclear envelope during mitotic exit and are a common consequence of chromosomal instability. MN are unstable due to errors in nuclear envelope organization and frequently rupture, leading to loss of compartmentalization, loss of nuclear functions, and major changes in genome stability and gene expression. However, recent work found that, even prior to rupture, nuclear processes can be severely defective in MN, which may contribute to rupture-associated defects and have lasting consequences for chromatin structure and function. In this review we discuss work that highlights nuclear function defects in intact MN, including their mechanisms and consequences, and how biases in chromosome missegregation into MN may affect the penetrance of these defects. Illuminating the nuclear environment of MN demonstrates that MN formation alone has major consequences for both the genome and cell and provides new insight into how nuclear content is regulated.
    DOI:  https://doi.org/10.1016/j.sbi.2024.102839
  21. Int J Mol Sci. 2024 May 09. pii: 5134. [Epub ahead of print]25(10):
    SKA3 Expression as a Prognostic Factor for Patients with Pancreatic Adenocarcinoma.
    Karolina Buchholz, Justyna Durślewicz, Anna Klimaszewska-Wiśniewska, Magdalena Wiśniewska, Maciej Słupski, Dariusz Grzanka.
      The spindle and kinetochore-associated complex subunit 3 (SKA3) is a protein essential for proper chromosome segregation during mitosis and thus responsible for maintaining genome stability. Although its involvement in the pathogenesis of various cancer types has been reported, the potential clinicopathological significance of SKA3 in pancreatic ductal adenocarcinoma (PDAC) has not been fully elucidated. Therefore, this study aimed to assess clinicopathological associations and prognostic value of SKA3 in PDAC. For this purpose, in-house immunohistochemical analysis on tissue macroarrays (TMAs), as well as a bioinformatic examination using publicly available RNA-Seq dataset, were performed. It was demonstrated that SKA3 expression at both mRNA and protein levels was significantly elevated in PDAC compared to control tissues. Upregulated mRNA expression constituted an independent unfavorable prognostic factor for the overall survival of PDAC patients, whereas altered SKA3 protein levels were associated with significantly better clinical outcomes. The last observation was particularly clear in the early-stage tumors. These findings render SKA3 a promising prognostic biomarker for patients with pancreatic ductal adenocarcinoma. However, further studies are needed to confirm this conclusion.
    Keywords:  SKA3; pancreatic adenocarcinoma; prognostic factor
    DOI:  https://doi.org/10.3390/ijms25105134
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