bims-micesi 2022-11-27 papers

bims-micesi

Biomed News

on Mitotic cell signalling

Issue of 2022–11–27
fourteen papers selected by
Valentina Piano, Uniklinik Köln

Chromosome segregation fidelity requires microtubule polyglutamylation by the cancer downregulated enzyme TTLL11.
Diversity is the spice of life: An overview of how cytokinesis regulation varies with cell type.
Automated Immunofluorescence Staining for Analysis of Mitotic Stages and Division Orientation in Brain Sections.
Centromere Chromatin Dynamics at a Glance.
Cell cycle: Making waves to coordinate the entry into mitosis.
Chromosome Inequality: Causes and Consequences of Non-Random Segregation Errors in Mitosis and Meiosis.
Minor Kinases with Major Roles in Cytokinesis Regulation.
Chromosome Tug of War: Dicentric Chromosomes and the Centromere Strength Hypothesis.
Mitotic phosphorylation inhibits the Golgi mannosidase MAN1A1.
Computational Biology Dynamics of Mps1 Kinase Molecular Interactions with Isoflavones Reveals a Chemical Scaffold with Potential to Develop New Therapeutics for the Treatment of Cancer.
Plant Lineage-Specific PIKMIN1 Drives APC/CCCS52A2 E3-Ligase Activity-Dependent Cell Division.
Uncoupling cell division and cytokinesis during germline development in metazoans.
Cytokinetic diversity in mammalian cells is revealed by the characterization of endogenous anillin, Ect2 and RhoA.
The role of anillin/Mid1p during medial division and cytokinesis: from fission yeast to cancer cells.

Nat Commun. 2022 Nov 21. 13(1): 7147

Chromosome segregation fidelity requires microtubule polyglutamylation by the cancer downregulated enzyme TTLL11.

Ivan Zadra, Senda Jimenez-Delgado, Miquel Anglada-Girotto, Carolina Segura-Morales, Zachary J Compton, Carsten Janke, Luis Serrano, Verena Ruprecht, Isabelle Vernos.

Regulation of microtubule (MT) dynamics is key for mitotic spindle assembly and faithful chromosome segregation. Here we show that polyglutamylation, a still understudied post-translational modification of spindle MTs, is essential to define their dynamics within the range required for error-free chromosome segregation. We identify TTLL11 as an enzyme driving MT polyglutamylation in mitosis and show that reducing TTLL11 levels in human cells or zebrafish embryos compromises chromosome segregation fidelity and impairs early embryonic development. Our data reveal a mechanism to ensure genome stability in normal cells that is compromised in cancer cells that systematically downregulate TTLL11. Our data suggest a direct link between MT dynamics regulation, MT polyglutamylation and two salient features of tumour cells, aneuploidy and chromosome instability (CIN).

DOI: https://doi.org/10.1038/s41467-022-34909-y
Front Cell Dev Biol. 2022 ;10 1007614

Diversity is the spice of life: An overview of how cytokinesis regulation varies with cell type.

Imge Ozugergin, Alisa Piekny.

  Cytokinesis is required to physically cleave a cell into two daughters at the end of mitosis. Decades of research have led to a comprehensive understanding of the core cytokinesis machinery and how it is regulated in animal cells, however this knowledge was generated using single cells cultured in vitro, or in early embryos before tissues develop. This raises the question of how cytokinesis is regulated in diverse animal cell types and developmental contexts. Recent studies of distinct cell types in the same organism or in similar cell types from different organisms have revealed striking differences in how cytokinesis is regulated, which includes different threshold requirements for the structural components and the mechanisms that regulate them. In this review, we highlight these differences with an emphasis on pathways that are independent of the mitotic spindle, and operate through signals associated with the cortex, kinetochores, or chromatin.

Keywords:  RhoA; actomyosin; chromatin; cytokinesis; mitosis; mitotic spindle

DOI:  https://doi.org/10.3389/fcell.2022.1007614
Methods Mol Biol. 2023 ;2583 63-79

Automated Immunofluorescence Staining for Analysis of Mitotic Stages and Division Orientation in Brain Sections.

Gabriela De la Cruz, Nana Nikolaishvili Feinberg, Scott E Williams.

  Microcephaly often results from mitotic defects in neuronal progenitors, frequently by decreasing proliferation rates or shifting cell fates. During neurogenesis, oriented cell division-the molecular control of mitotic spindle positioning to control the axis of division-represents an important mechanism to balance expansion of the progenitor pool with generating cellular diversity. While mostly studied in the context of cortical development, more recently, spindle orientation has emerged as a key player in the formation of other brain regions such as the cerebellum. Here we describe methods to perform automated dual-color fluorescent immunohistochemistry on murine cerebellar sections using the mitotic markers phospho-Histone H3 and Survivin, and detail analytical and statistical approaches to display and compare division orientation datasets.

Keywords:  Asymmetric cell division; Cerebellar granule neuron progenitors; Cerebellum; Division orientation; Granule cells; Microcephaly; Mitosis; Oriented cell division; Spindle orientation

DOI:  https://doi.org/10.1007/978-1-0716-2752-5_7
Epigenomes. 2022 Nov 03. pii: 39. [Epub ahead of print]6(4):

Centromere Chromatin Dynamics at a Glance.

Shivangi Shukla, Ashutosh Kumar.

  The centromere is a specialized DNA locus that ensures the faithful segregation of chromosomes during cell division. It does so by directing the assembly of an essential proteinaceous structure called the kinetochore. The centromere identity is primarily epigenetically defined by a nucleosome containing an H3 variant called CENP-A as well as by the interplay of several factors such as differential chromatin organization driven by CENP-A and H2A.Z, centromere-associated proteins, and post-translational modifications. At the centromere, CENP-A is not just a driving force for kinetochore assembly but also modifies the structural and dynamic properties of the centromeric chromatin, resulting in a distinctive chromatin organization. An additional level of regulation of the centromeric chromatin conformation is provided by post-translational modifications of the histones in the CENP-A nucleosomes. Further, H2A.Z is present in the regions flanking the centromere for heterochromatinization. In this review, we focus on the above-mentioned factors to describe how they contribute to the organization of the centromeric chromatin: CENP-A at the core centromere, post-translational modifications that decorate CENP-A, and the variant H2A.Z.

Keywords:  CENP-A; H2A.Z; PTM; centromere; heterochromatin; kinetochore

DOI:  https://doi.org/10.3390/epigenomes6040039
Curr Biol. 2022 Nov 21. pii: S0960-9822(22)01675-X. [Epub ahead of print]32(22): R1262-R1264

Cell cycle: Making waves to coordinate the entry into mitosis.

Zachary M Wilmott, Jordan W Raff.

How do very large cells coordinate their entry into mitosis? A new study shows that the bistability of the Cdk/Cyclin system allows cells to generate either 'trigger waves' or 'sweep waves' that drive cells into mitosis in different ways with distinct consequences.

DOI: https://doi.org/10.1016/j.cub.2022.10.030
Cells. 2022 Nov 11. pii: 3564. [Epub ahead of print]11(22):

Chromosome Inequality: Causes and Consequences of Non-Random Segregation Errors in Mitosis and Meiosis.

Sjoerd J Klaasen, Geert J P L Kops.

  Aneuploidy is a hallmark of cancer and a major cause of miscarriages in humans. It is caused by chromosome segregation errors during cell divisions. Evidence is mounting that the probability of specific chromosomes undergoing a segregation error is non-random. In other words, some chromosomes have a higher chance of contributing to aneuploid karyotypes than others. This could have important implications for the origins of recurrent aneuploidy patterns in cancer and developing embryos. Here, we review recent progress in understanding the prevalence and causes of non-random chromosome segregation errors in mammalian mitosis and meiosis. We evaluate its potential impact on cancer and human reproduction and discuss possible research avenues.

Keywords:  aneuploidy; cancer; chromosomal instability; development; embryo; meiosis; mitosis; non-random segregation errors

DOI:  https://doi.org/10.3390/cells11223564
Cells. 2022 Nov 17. pii: 3639. [Epub ahead of print]11(22):

Minor Kinases with Major Roles in Cytokinesis Regulation.

Stefano Sechi, Roberto Piergentili, Maria Grazia Giansanti.

  Cytokinesis, the conclusive act of cell division, allows cytoplasmic organelles and chromosomes to be faithfully partitioned between two daughter cells. In animal organisms, its accurate regulation is a fundamental task for normal development and for preventing aneuploidy. Cytokinesis failures produce genetically unstable tetraploid cells and ultimately result in chromosome instability, a hallmark of cancer cells. In animal cells, the assembly and constriction of an actomyosin ring drive cleavage furrow ingression, resulting in the formation of a cytoplasmic intercellular bridge, which is severed during abscission, the final event of cytokinesis. Kinase-mediated phosphorylation is a crucial process to orchestrate the spatio-temporal regulation of the different stages of cytokinesis. Several kinases have been described in the literature, such as cyclin-dependent kinase, polo-like kinase 1, and Aurora B, regulating both furrow ingression and/or abscission. However, others exist, with well-established roles in cell-cycle progression but whose specific role in cytokinesis has been poorly investigated, leading to considering these kinases as "minor" actors in this process. Yet, they deserve additional attention, as they might disclose unexpected routes of cell division regulation. Here, we summarize the role of multifunctional kinases in cytokinesis with a special focus on those with a still scarcely defined function during cell cleavage. Moreover, we discuss their implication in cancer.

Keywords:  P21-activated kinases (PAK); cancer; casein kinase 2 (CK2); checkpoint kinase 2 (Chk2); cytokinesis

DOI:  https://doi.org/10.3390/cells11223639
Cells. 2022 Nov 10. pii: 3550. [Epub ahead of print]11(22):

Chromosome Tug of War: Dicentric Chromosomes and the Centromere Strength Hypothesis.

Hunter J Hill, Kent G Golic.

  It has been 70 years since the concept of varied centromere strengths was introduced based on the behavior of dicentric chromosomes. One of the key conclusions from those early experiments was that some centromeres could pull with sufficient force to break a dicentric chromosome bridge, while others could not. In the ensuing decades there have been numerous studies to characterize strengths of the various components involved, such as the spindle, the kinetochore, and the chromosome itself. We review these various measurements to determine if the conclusions about centromere strength are supported by current evidence, with special attention to characterization of Drosophila melanogaster kinetochores upon which the original conclusions were based.

Keywords:  CENPA; centromere; dicentric chromosome; kinetochore; microtubules; spindle

DOI:  https://doi.org/10.3390/cells11223550
Cell Rep. 2022 Nov 22. pii: S2211-1247(22)01553-4. [Epub ahead of print]41(8): 111679

Mitotic phosphorylation inhibits the Golgi mannosidase MAN1A1.

Shijiao Huang, Yoshimi Haga, Jie Li, Jianchao Zhang, Hye Kyong Kweon, Junichi Seino, Hiroto Hirayama, Morihisa Fujita, Kelley W Moremen, Philip Andrews, Tadashi Suzuki, Yanzhuang Wang.

  N-glycans are processed mainly in the Golgi, and a well-organized Golgi structure is required for accurate glycosylation. However, during mitosis the Golgi undergoes severe fragmentation. The resulting trafficking block leads to an extended exposure of cargo molecules to Golgi enzymes. It is unclear how cells avoid glycosylation defects during mitosis. In this study, we report that Golgi α-1,2-mannosidase IA (MAN1A1), the first enzyme that cargo proteins encounter once arriving the Golgi, is phosphorylated at serine 12 by CDK1 in mitosis, which attenuates its activity, affects the production of glycan isomers, and reduces its interaction with the subsequent glycosyltransferase, MGAT1. Expression of wild-type MAN1A1, but not its phosphomimetic mutant, rescues the glycosylation defects in mannosidase I-deficient cells, whereas expression of its phosphorylation-deficient mutant in mitosis increases the formation of complex glycans. Our study reveals that glycosylation is regulated by cytosolic signaling during the cell cycle.

Keywords:  CP: Cell biology; Golgi; glycosylation; isomer; mannosidase; mitosis; oligomerization; phosphorylation

DOI:  https://doi.org/10.1016/j.celrep.2022.111679
Int J Mol Sci. 2022 Nov 17. pii: 14228. [Epub ahead of print]23(22):

Computational Biology Dynamics of Mps1 Kinase Molecular Interactions with Isoflavones Reveals a Chemical Scaffold with Potential to Develop New Therapeutics for the Treatment of Cancer.

Lauren Pugh, Alisha Pancholi, Priscila Celeste Purat, Sandra Agudo-Alvarez, Raúl Benito-Arenas, Agatha Bastida, Victor M Bolanos-Garcia.

  The protein kinase Mps1 (monopolar spindle 1) is an important regulator of the Spindle Assembly Checkpoint (SAC), the evolutionary conserved checkpoint system of higher organisms that monitors the proper bipolar attachment of all chromosomes to the mitotic spindle during cell division. Defects in the catalytic activity and the transcription regulation of Mps1 are associated with genome instability, aneuploidy, and cancer. Moreover, multiple Mps1 missense and frameshift mutations have been reported in a wide range of types of cancer of different tissue origin. Due to these features, Mps1 arises as one promising drug target for cancer therapy. In this contribution, we developed a computational biology approach to study the dynamics of human Mps1 kinase interaction with isoflavones, a class of natural flavonoids, and compared their predicted mode of binding with that observed in the crystal structure of Mps1 in complex with reversine, a small-sized inhibitor of Mps1 and Aurora B kinases. We concluded that isoflavones define a chemical scaffold that can be used to develop new Mps1 inhibitors for the treatment of cancer associated with Mps1 amplification and aberrant chromosome segregation. In a broader context, the present report illustrates how modern chemoinformatics approaches can accelerate drug development in oncology.

Keywords:  Mps1; bioinformatics; cancer; flavonoid-like compounds; molecular docking; poor prognosis tumours

DOI:  https://doi.org/10.3390/ijms232214228
Plant Physiol. 2022 Nov 24. pii: kiac528. [Epub ahead of print]

Plant Lineage-Specific PIKMIN1 Drives APC/CCCS52A2 E3-Ligase Activity-Dependent Cell Division.

Alex Willems, Yuanke Liang, Jefri Heyman, Thomas Depuydt, Thomas Eekhout, Balkan Canher, Hilde Van den Daele, Ilse Vercauteren, Klaas Vandepoele, Lieven De Veylder.

The anaphase-promoting complex/cyclosome (APC/C) marks key cell cycle proteins for proteasomal breakdown, thereby ensuring unidirectional progression through the cell cycle. Its target recognition is temporally regulated by activating subunits, one of which is called CELL CYCLE SWITCH 52 A2 (CCS52A2). We sought to expand the knowledge on the APC/C by using the severe growth phenotypes of CCS52A2-deficient Arabidopsis (Arabidopsis thaliana) plants as a readout in a suppressor mutagenesis screen, resulting in the identification of the previously undescribed gene called PIKMIN1 (PKN1). PKN1 deficiency rescues the disorganized root stem cell phenotype of the ccs52a2-1 mutant, whereas an excess of PKN1 inhibits growth of ccs52a2-1 plants, indicating the need for control of PKN1 abundance for proper development. Accordingly, the lack of PKN1 in a wild-type background negatively impacts cell division, while its systemic overexpression promotes proliferation. PKN1 shows a cell cycle phase-dependent accumulation pattern, localizing to microtubular structures, including the preprophase band, the mitotic spindle, and phragmoplast. PKN1 is conserved throughout the plant kingdom, with its function in cell division being evolutionary conserved in the liverwort Marchantia polymorpha. Our data thus demonstrate that PKN1 represents a novel, plant-specific gene with a role in cell division that is likely proteolytically controlled by the CCS52A2-activated APC/C.

DOI: https://doi.org/10.1093/plphys/kiac528
Front Cell Dev Biol. 2022 ;10 1001689

Uncoupling cell division and cytokinesis during germline development in metazoans.

Abigail R Gerhold, Jean-Claude Labbé, Ramya Singh.

  The canonical eukaryotic cell cycle ends with cytokinesis, which physically divides the mother cell in two and allows the cycle to resume in the newly individualized daughter cells. However, during germline development in nearly all metazoans, dividing germ cells undergo incomplete cytokinesis and germ cells stay connected by intercellular bridges which allow the exchange of cytoplasm and organelles between cells. The near ubiquity of incomplete cytokinesis in animal germ lines suggests that this is an ancient feature that is fundamental for the development and function of this tissue. While cytokinesis has been studied for several decades, the mechanisms that enable regulated incomplete cytokinesis in germ cells are only beginning to emerge. Here we review the current knowledge on the regulation of germ cell intercellular bridge formation, focusing on findings made using mouse, Drosophila melanogaster and Caenorhabditis elegans as experimental systems.

Keywords:  germ cells; germline development; incomplete cytokinesis; intercellular bridges; metazoan

DOI:  https://doi.org/10.3389/fcell.2022.1001689
Open Biol. 2022 Nov;12(11): 220247

Cytokinetic diversity in mammalian cells is revealed by the characterization of endogenous anillin, Ect2 and RhoA.

Mathieu C Husser, Imge Ozugergin, Tiziana Resta, Vincent J J Martin, Alisa J Piekny.

  Cytokinesis is required to physically separate the daughter cells at the end of mitosis. This crucial process requires the assembly and ingression of an actomyosin ring, which must occur with high fidelity to avoid aneuploidy and cell fate changes. Most of our knowledge of mammalian cytokinesis was generated using over-expressed transgenes in HeLa cells. Over-expression can introduce artefacts, while HeLa are cancerous human cells that have lost their epithelial identity, and the mechanisms controlling cytokinesis in these cells could be vastly different from other cell types. Here, we tagged endogenous anillin, Ect2 and RhoA with mNeonGreen and characterized their localization during cytokinesis for the first time in live human cells. Comparing anillin localization in multiple cell types revealed cytokinetic diversity with differences in the duration and symmetry of ring closure, and the timing of cortical recruitment. Our findings show that the breadth of anillin correlates with the rate of ring closure, and support models where cell size or ploidy affects the cortical organization, and intrinsic mechanisms control the symmetry of ring closure. This work highlights the need to study cytokinesis in more diverse cell types, which will be facilitated by the reagents generated for this study.

Keywords:  CRISPR; RhoA; actomyosin; cytokinesis; microscopy

DOI:  https://doi.org/10.1098/rsob.220247
Cell Cycle. 2022 Nov 25. 1-12

The role of anillin/Mid1p during medial division and cytokinesis: from fission yeast to cancer cells.

Imane M Rezig, Wandiahyel G Yaduma, Gwyn W Gould, Christopher J McInerny.

  Cytokinesis is the final stage of cell division cycle when cellular constituents are separated to produce two daughter cells. This process is driven by the formation and constriction of a contractile ring. Progression of these events is controlled by mechanisms and proteins that are evolutionary conserved in eukaryotes from fungi to humans. Genetic and molecular studies in different model organisms identified essential cytokinesis genes, with several conserved proteins, including the anillin/Mid1p proteins, constituting the core cytokinetic machinery. The fission yeast Schizosaccharomyces pombe represents a well-established model organism to study eukaryotic cell cycle regulation. Cytokinesis in fission yeast and mammalian cells depends on the placement, assembly, maturation, and constriction of a medially located actin-myosin contractile ring (ACR). Here, we review aspects of the ACR assembly and cytokinesis process in fission yeast and consider the regulation of such events in mammalian cells. First, we briefly describe the role of anillin during mammalian ACR assembly and cytokinesis. Second, we describe different aspects of the anillin-like protein Mid1p regulation during the S. pombe cell cycle, including its structure, function, and phospho-regulation. Third, we briefly discuss Mid1pindependent ACR assembly in S. pombe. Fourth, we highlight emerging studies demonstrating the roles of anillin in human tumourigenesis introducing anillin as a potential drug target for cancer treatment. Collectively, we provide an overview of the current understanding of medial division and cytokinesis in S. pombe and suggest the implications of these observations in other eukaryotic organisms, including humans.

Keywords:  Mid1p; anillin; cytokinesis; fission yeast

DOI:  https://doi.org/10.1080/15384101.2022.2147655