bims-micesi Biomed News
on Mitotic cell signalling
Issue of 2023–08–20
nine papers selected by
Valentina Piano, Uniklinik Köln
  1. Phosphorylation controls spatial and temporal activities of motor-PRC1 complexes to complete mitosis.
  2. Hornerin mediates phosphorylation of the polo-box domain in Plk1 by Chk1 to induce death in mitosis.
  3. Urban dust particles disrupt mitotic progression by dysregulating Aurora kinase B-related functions.
  4. AMBRA1 phosphorylation by CDK1 and PLK1 regulates mitotic spindle orientation.
  5. The CENP-A nucleosome: where and when it happens during the inner kinetochore's assembly.
  6. A force-sensitive mutation reveals a spindle assembly checkpoint-independent role for dynein in anaphase progression.
  7. GATA2 mitotic bookmarking is required for definitive haematopoiesis.
  8. Mechanistic model for nuclear migration in hyphae during mitosis.
  9. Centromere-specifying nucleosomes persist in aging mouse oocytes in the absence of nascent assembly.
  1. EMBO J. 2023 Aug 18. e113647
    Phosphorylation controls spatial and temporal activities of motor-PRC1 complexes to complete mitosis.
    Agata Gluszek-Kustusz, Benjamin Craske, Thibault Legal, Toni McHugh, Julie Pi Welburn.
      During mitosis, spindle architecture alters as chromosomes segregate into daughter cells. The microtubule crosslinker protein regulator of cytokinesis 1 (PRC1) is essential for spindle stability, chromosome segregation and completion of cytokinesis, but how it recruits motors to the central spindle to coordinate the segregation of chromosomes is unknown. Here, we combine structural and cell biology approaches to show that the human CENP-E motor, which is essential for chromosome capture and alignment by microtubules, binds to PRC1 through a conserved hydrophobic motif. This binding mechanism is also used by Kinesin-4 Kif4A:PRC1. Using in vitro reconstitution, we demonstrate that CENP-E slides antiparallel PRC1-crosslinked microtubules. We find that the regulation of CENP-E -PRC1 interaction is spatially and temporally coupled with relocalization to overlapping microtubules in anaphase. Finally, we demonstrate that the PRC1-microtubule motor interaction is essential in anaphase to control chromosome partitioning, retain central spindle integrity and ensure cytokinesis. Taken together our findings reveal the molecular basis for the cell cycle regulation of motor-PRC1 complexes to couple chromosome segregation and cytokinesis.
    Keywords:  kinesin; microtubule; mitosis; phosphorylation; spindle
    DOI:  https://doi.org/10.15252/embj.2023113647
  2. Cell Death Differ. 2023 Aug 18.
    Hornerin mediates phosphorylation of the polo-box domain in Plk1 by Chk1 to induce death in mitosis.
    Haiyu Song, Eun Ho Kim, Jihee Hong, Dasom Gwon, Jee Won Kim, Gyu-Un Bae, Chang-Young Jang.
      The centrosome assembles a bipolar spindle for faithful chromosome segregation during mitosis. To prevent the inheritance of DNA damage, the DNA damage response (DDR) triggers programmed spindle multipolarity and concomitant death in mitosis through a poorly understood mechanism. We identified hornerin, which forms a complex with checkpoint kinase 1 (Chk1) and polo-like kinase 1 (Plk1) to mediate phosphorylation at the polo-box domain (PBD) of Plk1, as the link between the DDR and death in mitosis. We demonstrate that hornerin mediates DDR-induced precocious centriole disengagement through a dichotomous mechanism that includes sequestration of Sgo1 and Plk1 in the cytoplasm through phosphorylation of the PBD in Plk1 by Chk1. Phosphorylation of the PBD in Plk1 abolishes the interaction with Sgo1 and phosphorylation-dependent Sgo1 translocation to the centrosome, leading to precocious centriole disengagement and spindle multipolarity. Mechanistically, hornerin traps phosphorylated Plk1 in the cytoplasm. Furthermore, PBD phosphorylation inactivates Plk1 and disrupts Cep192::Aurora A::Plk1 complex translocation to the centrosome and concurrent centrosome maturation. Remarkably, hornerin depletion leads to chemoresistance against DNA damaging agents by attenuating DDR-induced death in mitosis. These results reveal how the DDR eradicates mitotic cells harboring DNA damage to ensure genome integrity during cell division.
    DOI:  https://doi.org/10.1038/s41418-023-01208-y
  3. J Hazard Mater. 2023 Aug 06. pii: S0304-3894(23)01521-2. [Epub ahead of print]459 132238
    Urban dust particles disrupt mitotic progression by dysregulating Aurora kinase B-related functions.
    Jaewook Ryu, Seung Hyeun Lee, Sungyeon Kim, Joo-Won Jeong, Kyung Sook Kim, Seungyoon Nam, Ja-Eun Kim.
      Particulate matter (PM), a major component of outdoor air pollution, damages DNA and increases the risk of cancer. Although the harmful effects of PM at the genomic level are known, the detailed mechanism by which PM affects chromosomal stability remains unclear. In this study, we investigated the novel effects of PM on mitotic progression and identified the underlying mechanisms. Gene set enrichment analysis of lung cancer patients residing in countries with high PM concentrations revealed the downregulation of genes associated with mitosis and mitotic structures. We also showed that exposure of lung cancer cells in vitro to urban dust particles (UDPs) inhibits cell proliferation through a prolonged M phase. The mitotic spindles in UDP-treated cells were hyperstabilized, and the number of centrioles increased. The rate of ingression of the cleavage furrow and actin clearance from the polar cortex was reduced significantly. The defects in mitotic progression were attributed to inactivation of Aurora B at kinetochore during early mitosis, and spindle midzone and midbody during late mitosis. While previous studies demonstrated possible links between PM and mitosis, they did not specifically identify the dysregulation of spatiotemporal dynamics of mitotic proteins and structures (e.g., microtubules, centrosomes, cleavage furrow, and equatorial and polar cortex), which results in the accumulation of chromosomal instability, ultimately contributing to carcinogenicity. The data highlight the novel scientific problem of PM-induced mitotic disruption. Additionally, we introduce a practical visual method for assessing the genotoxic outcomes of airborne pollutants, which has implications for future environmental and public health research.
    Keywords:  Air pollution; Airborne particulate matter; Chromosomal instability; Genotoxicity; Mitosis
    DOI:  https://doi.org/10.1016/j.jhazmat.2023.132238
  4. Cell Mol Life Sci. 2023 Aug 16. 80(9): 251
    AMBRA1 phosphorylation by CDK1 and PLK1 regulates mitotic spindle orientation.
    Fiorella Faienza, Federica Polverino, Girish Rajendraprasad, Giacomo Milletti, Zehan Hu, Barbara Colella, Deborah Gargano, Flavie Strappazzon, Salvatore Rizza, Mette Vixø Vistesen, Yonglun Luo, Manuela Antonioli, Valentina Cianfanelli, Caterina Ferraina, Gian Maria Fimia, Giuseppe Filomeni, Daniela De Zio, Joern Dengjel, Marin Barisic, Giulia Guarguaglini, Sabrina Di Bartolomeo, Francesco Cecconi.
      AMBRA1 is a crucial factor for nervous system development, and its function has been mainly associated with autophagy. It has been also linked to cell proliferation control, through its ability to regulate c-Myc and D-type cyclins protein levels, thus regulating G1-S transition. However, it remains still unknown whether AMBRA1 is differentially regulated during the cell cycle, and if this pro-autophagy protein exerts a direct role in controlling mitosis too. Here we show that AMBRA1 is phosphorylated during mitosis on multiple sites by CDK1 and PLK1, two mitotic kinases. Moreover, we demonstrate that AMBRA1 phosphorylation at mitosis is required for a proper spindle function and orientation, driven by NUMA1 protein. Indeed, we show that the localization and/or dynamics of NUMA1 are strictly dependent on AMBRA1 presence, phosphorylation and binding ability. Since spindle orientation is critical for tissue morphogenesis and differentiation, our findings could account for an additional role of AMBRA1 in development and cancer ontogenesis.
    Keywords:  Cell cycle; Mitotic kinases; Mitotic spindle; NUMA1; Phosphorylation
    DOI:  https://doi.org/10.1007/s00018-023-04878-6
  5. Trends Biochem Sci. 2023 Aug 16. pii: S0968-0004(23)00176-7. [Epub ahead of print]
    The CENP-A nucleosome: where and when it happens during the inner kinetochore's assembly.
    Seyit Kale, Ramachandran Boopathi, Edwige Belotti, Imtiaz Nisar Lone, Mohamed Graies, Maria Schröder, Maria Petrova, Christophe Papin, Jan Bednar, Iva Ugrinova, Ali Hamiche, Stefan Dimitrov.
      CENP-A is an essential histone variant that replaces the canonical H3 at the centromeres and marks these regions epigenetically. The CENP-A nucleosome is the specific building block of centromeric chromatin, and it is recognized by CENP-C and CENP-N, two components of the constitutive centromere-associated network (CCAN), the first protein layer of the kinetochore. Recent proposals of the yeast and human (h)CCAN structures position the assembly on exposed DNA, suggesting an elusive spatiotemporal recognition. We summarize the data on the structural organization of the CENP-A nucleosome and the binding of CENP-C and CENP-N. The latter posits an apparent contradiction in engaging the CENP-A nucleosome versus the CCAN. We propose a reconciliatory model for the assembly of CCAN on centromeric chromatin.
    Keywords:  CCAN complex; CENP-A nucleosome; chromatin; histone variants; mitosis
    DOI:  https://doi.org/10.1016/j.tibs.2023.07.010
  6. bioRxiv. 2023 Aug 04. pii: 2023.08.03.551815. [Epub ahead of print]
    A force-sensitive mutation reveals a spindle assembly checkpoint-independent role for dynein in anaphase progression.
    David Salvador-Garcia, Li Jin, Andrew Hensley, Mert Gölcük, Emmanuel Gallaud, Sami Chaaban, Fillip Port, Alessio Vagnoni, Vicente José Planelles-Herrero, Mark A McClintock, Emmanuel Derivery, Andrew P Carter, Régis Giet, Mert Gür, Ahmet Yildiz, Simon L Bullock.
      The cytoplasmic dynein-1 (dynein) motor organizes cells by shaping microtubule networks and moving a large variety of cargoes along them. However, dynein's diverse roles complicate in vivo studies of its functions significantly. To address this issue, we have used gene editing to generate a series of missense mutations in Drosophila Dynein heavy chain (Dhc). We find that mutations associated with human neurological disease cause a range of defects in larval and adult flies, including impaired cargo trafficking in neurons. We also describe a novel mutation in the microtubule-binding domain (MTBD) of Dhc that, remarkably, causes metaphase arrest of mitotic spindles in the embryo but does not impair other dynein-dependent processes. We demonstrate that the mitotic arrest is independent of dynein's well-established roles in silencing the spindle assembly checkpoint. In vitro reconstitution and optical trapping assays reveal that the mutation only impairs the performance of dynein under load. In silico all-atom molecular dynamics simulations show that this effect correlates with increased flexibility of the MTBD, as well as an altered orientation of the stalk domain, with respect to the microtubule. Collectively, our data point to a novel role of dynein in anaphase progression that depends on the motor operating in a specific load regime. More broadly, our work illustrates how cytoskeletal transport processes can be dissected in vivo by manipulating mechanical properties of motors.
    DOI:  https://doi.org/10.1101/2023.08.03.551815
  7. Nat Commun. 2023 Aug 14. 14(1): 4645
    GATA2 mitotic bookmarking is required for definitive haematopoiesis.
    Rita Silvério-Alves, Ilia Kurochkin, Anna Rydström, Camila Vazquez Echegaray, Jakob Haider, Matthew Nicholls, Christina Rode, Louise Thelaus, Aida Yifter Lindgren, Alexandra Gabriela Ferreira, Rafael Brandão, Jonas Larsson, Marella F T R de Bruijn, Javier Martin-Gonzalez, Carlos-Filipe Pereira.
      In mitosis, most transcription factors detach from chromatin, but some are retained and bookmark genomic sites. Mitotic bookmarking has been implicated in lineage inheritance, pluripotency and reprogramming. However, the biological significance of this mechanism in vivo remains unclear. Here, we address mitotic retention of the hemogenic factors GATA2, GFI1B and FOS during haematopoietic specification. We show that GATA2 remains bound to chromatin throughout mitosis, in contrast to GFI1B and FOS, via C-terminal zinc finger-mediated DNA binding. GATA2 bookmarks a subset of its interphase targets that are co-enriched for RUNX1 and other regulators of definitive haematopoiesis. Remarkably, homozygous mice harbouring the cyclin B1 mitosis degradation domain upstream Gata2 partially phenocopy knockout mice. Degradation of GATA2 at mitotic exit abolishes definitive haematopoiesis at aorta-gonad-mesonephros, placenta and foetal liver, but does not impair yolk sac haematopoiesis. Our findings implicate GATA2-mediated mitotic bookmarking as critical for definitive haematopoiesis and highlight a dependency on bookmarkers for lineage commitment.
    DOI:  https://doi.org/10.1038/s41467-023-40391-x
  8. Phys Rev E. 2023 Jul;108(1-1): 014401
    Mechanistic model for nuclear migration in hyphae during mitosis.
    Subhendu Som, Raja Paul.
      Saccharomyces cerevisiae and Candida albicans, the two well-known human pathogens, can be found in all three morphologies, i.e., yeast, pseudohyphae, and true hyphae. The cylindrical daughter-bud (germ tube) grows very long for true hyphae, and the cell cycle is delayed compared to the other two morphologies. The place of the nuclear division is specific for true hyphae determined by the position of the septin ring. However, the septin ring can localize anywhere inside the germ tube, unlike the mother-bud junction in budding yeast. Since the nucleus often migrates a long path in the hyphae, the underlying mechanism must be robust for executing mitosis in a timely manner. We explore the mechanism of nuclear migration through hyphae in light of mechanical interactions between astral microtubules and the cell cortex. We report that proper migration through constricted hyphae requires a large dynein pull applied on the astral microtubules from the hyphal cortex. This is achieved when the microtubules frequently slide along the hyphal cortex so that a large population of dyneins actively participate, pulling on them. Simulation shows timely migration when the dyneins from the mother cortex do not participate in pulling on the microtubules. These findings are robust for long migration and positioning of the nucleus in the germ tube at the septin ring.
    DOI:  https://doi.org/10.1103/PhysRevE.108.014401
  9. Curr Biol. 2023 Aug 04. pii: S0960-9822(23)00971-5. [Epub ahead of print]
    Centromere-specifying nucleosomes persist in aging mouse oocytes in the absence of nascent assembly.
    Arunika Das, Katelyn G Boese, Kikue Tachibana, Sung Hee Baek, Michael A Lampson, Ben E Black.
      Centromeres direct genetic inheritance but are not themselves genetically encoded. Instead, centromeres are defined epigenetically by the presence of a histone H3 variant, CENP-A.1 In cultured somatic cells, an established paradigm of cell-cycle-coupled propagation maintains centromere identity: CENP-A is partitioned between sisters during replication and replenished by new assembly, which is restricted to G1. The mammalian female germ line challenges this model because of the cell-cycle arrest between pre-meiotic S phase and the subsequent G1, which can last for the entire reproductive lifespan (months to decades). New CENP-A chromatin assembly maintains centromeres during prophase I in worm and starfish oocytes,2,3 suggesting that a similar process may be required for centromere inheritance in mammals. To test this hypothesis, we developed an oocyte-specific conditional knockout (cKO) mouse for Mis18α, an essential component of the assembly machinery. We find that embryos derived from Mis18α knockout oocytes fail to assemble CENP-A nucleosomes prior to zygotic genome activation (ZGA), validating the knockout model. We show that deletion of Mis18α in the female germ line at the time of birth has no impact on centromeric CENP-A nucleosome abundance, even after 6-8 months of aging. In addition, there is no detectable detriment to fertility. Thus, centromere chromatin is maintained long-term, independent of new assembly during the extended prophase I arrest in mouse oocytes.
    Keywords:  centromeres; meiosis; nucleosomes; oocytes; protein stability; reproductive aging
    DOI:  https://doi.org/10.1016/j.cub.2023.07.032
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