Cells

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18 pages, 905 KiB

Open AccessFeature PaperReview

The Mitotic Apparatus and Kinetochores in Microcephaly and Neurodevelopmental Diseases

by Francesca Degrassi, Michela Damizia and Patrizia Lavia

Cells 2020, 9(1), 49; https://doi.org/10.3390/cells9010049 - 24 Dec 2019

Cited by 18 | Viewed by 4459

Regulators of mitotic division, when dysfunctional or expressed in a deregulated manner (over- or underexpressed) in somatic cells, cause chromosome instability, which is a predisposing condition to cancer that is associated with unrestricted proliferation. Genes encoding mitotic regulators are growingly implicated in neurodevelopmental [...] Read more.

Regulators of mitotic division, when dysfunctional or expressed in a deregulated manner (over- or underexpressed) in somatic cells, cause chromosome instability, which is a predisposing condition to cancer that is associated with unrestricted proliferation. Genes encoding mitotic regulators are growingly implicated in neurodevelopmental diseases. Here, we briefly summarize existing knowledge on how microcephaly-related mitotic genes operate in the control of chromosome segregation during mitosis in somatic cells, with a special focus on the role of kinetochore factors. Then, we review evidence implicating mitotic apparatus- and kinetochore-resident factors in the origin of congenital microcephaly. We discuss data emerging from these works, which suggest a critical role of correct mitotic division in controlling neuronal cell proliferation and shaping the architecture of the central nervous system. Full article

(This article belongs to the Special Issue Molecular Regulation of Mitosis and Its Role in Disease)

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15 pages, 2618 KiB

Open AccessReview

The cGAS Paradox: Contrasting Roles for cGAS-STING Pathway in Chromosomal Instability

by Christy Hong, Andrea E. Tijhuis and Floris Foijer

Cells 2019, 8(10), 1228; https://doi.org/10.3390/cells8101228 - 10 Oct 2019

Cited by 33 | Viewed by 10591

Abstract

Chromosomal instability (CIN) is an intricate phenomenon that is often found in human cancer, characterized by persisting errors in chromosome segregation. This ongoing chromosome mis-segregation results in structural and numerical chromosomal abnormalities that have been widely described to promote tumor evolution. In addition [...] Read more.

Chromosomal instability (CIN) is an intricate phenomenon that is often found in human cancer, characterized by persisting errors in chromosome segregation. This ongoing chromosome mis-segregation results in structural and numerical chromosomal abnormalities that have been widely described to promote tumor evolution. In addition to being a driver of tumor evolution, recent evidence demonstrates CIN to be the central node of the crosstalk between a tumor and its surrounding microenvironment, as mediated by the cGAS-STING pathway. The role that cGAS-STING signaling exerts on CIN tumors is both complex and paradoxical. On one hand, the cGAS-STING axis promotes the clearance of CIN tumors through recruitment of immune cells, thus suppressing tumor progression. On the other hand, the cGAS-STING pathway has been described to be the major regulator in the promotion of metastasis of CIN tumors. Here, we review this dual role of the cGAS-STING pathway in the context of chromosomal instability and discuss the potential therapeutic implications of cGAS-STING signaling for targeting CIN tumors. Full article

(This article belongs to the Special Issue Molecular Regulation of Mitosis and Its Role in Disease)

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11 pages, 1026 KiB

Open AccessReview

How Cells Handle DNA Breaks during Mitosis: Detection, Signaling, Repair, and Fate Choice

by Ruth Thompson, Rachel Gatenby and Samuel Sidi

Cells 2019, 8(9), 1049; https://doi.org/10.3390/cells8091049 - 7 Sep 2019

Cited by 11 | Viewed by 5533

Abstract

Mitosis is controlled by a complex series of signaling pathways but mitotic control following DNA damage remains poorly understood. Effective DNA damage sensing and repair is integral to survival but is largely thought to occur primarily in interphase and be repressed during mitosis [...] Read more.

Mitosis is controlled by a complex series of signaling pathways but mitotic control following DNA damage remains poorly understood. Effective DNA damage sensing and repair is integral to survival but is largely thought to occur primarily in interphase and be repressed during mitosis due to the risk of telomere fusion. There is, however, increasing evidence to suggest tight control of mitotic progression in the incidence of DNA damage, whether induced in mitotic cells or having progressed from failed interphase checkpoints. Here we will discuss what is known to date about signaling pathways controlling mitotic progression and resulting cell fate in the incidence of mitotic DNA damage. Full article

(This article belongs to the Special Issue Molecular Regulation of Mitosis and Its Role in Disease)

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19 pages, 870 KiB

Open AccessReview

Keeping the Centromere under Control: A Promising Role for DNA Methylation

by Andrea Scelfo and Daniele Fachinetti

Cells 2019, 8(8), 912; https://doi.org/10.3390/cells8080912 - 16 Aug 2019

Cited by 33 | Viewed by 8174

Abstract

In order to maintain cell and organism homeostasis, the genetic material has to be faithfully and equally inherited through cell divisions while preserving its integrity. Centromeres play an essential task in this process; they are special sites on chromosomes where kinetochores form on [...] Read more.

In order to maintain cell and organism homeostasis, the genetic material has to be faithfully and equally inherited through cell divisions while preserving its integrity. Centromeres play an essential task in this process; they are special sites on chromosomes where kinetochores form on repetitive DNA sequences to enable accurate chromosome segregation. Recent evidence suggests that centromeric DNA sequences, and epigenetic regulation of centromeres, have important roles in centromere physiology. In particular, DNA methylation is abundant at the centromere, and aberrant DNA methylation, observed in certain tumors, has been correlated to aneuploidy and genomic instability. In this review, we evaluate past and current insights on the relationship between centromere function and the DNA methylation pattern of its underlying sequences. Full article

(This article belongs to the Special Issue Molecular Regulation of Mitosis and Its Role in Disease)

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33 pages, 2505 KiB

Open AccessFeature PaperReview

Interplay between Phosphatases and the Anaphase-Promoting Complex/Cyclosome in Mitosis

by Meghna Kataria and Hiroyuki Yamano

Cells 2019, 8(8), 814; https://doi.org/10.3390/cells8080814 - 2 Aug 2019

Cited by 13 | Viewed by 6555

Abstract

Accurate division of cells into two daughters is a process that is vital to propagation of life. Protein phosphorylation and selective degradation have emerged as two important mechanisms safeguarding the delicate choreography of mitosis. Protein phosphatases catalyze dephosphorylation of thousands of sites on [...] Read more.

Accurate division of cells into two daughters is a process that is vital to propagation of life. Protein phosphorylation and selective degradation have emerged as two important mechanisms safeguarding the delicate choreography of mitosis. Protein phosphatases catalyze dephosphorylation of thousands of sites on proteins, steering the cells through establishment of the mitotic phase and exit from it. A large E3 ubiquitin ligase, the anaphase-promoting complex/cyclosome (APC/C) becomes active during latter stages of mitosis through G1 and marks hundreds of proteins for destruction. Recent studies have revealed the complex interregulation between these two classes of enzymes. In this review, we highlight the direct and indirect mechanisms by which phosphatases and the APC/C mutually influence each other to ensure accurate spatiotemporal and orderly progression through mitosis, with a particular focus on recent insights and conceptual advances. Full article

(This article belongs to the Special Issue Molecular Regulation of Mitosis and Its Role in Disease)

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20 pages, 1361 KiB

Open AccessReview

How Does SUMO Participate in Spindle Organization?

by Ariane Abrieu and Dimitris Liakopoulos

Cells 2019, 8(8), 801; https://doi.org/10.3390/cells8080801 - 31 Jul 2019

Cited by 10 | Viewed by 4690

Abstract

The ubiquitin-like protein SUMO is a regulator involved in most cellular mechanisms. Recent studies have discovered new modes of function for this protein. Of particular interest is the ability of SUMO to organize proteins in larger assemblies, as well as the role of [...] Read more.

The ubiquitin-like protein SUMO is a regulator involved in most cellular mechanisms. Recent studies have discovered new modes of function for this protein. Of particular interest is the ability of SUMO to organize proteins in larger assemblies, as well as the role of SUMO-dependent ubiquitylation in their disassembly. These mechanisms have been largely described in the context of DNA repair, transcriptional regulation, or signaling, while much less is known on how SUMO facilitates organization of microtubule-dependent processes during mitosis. Remarkably however, SUMO has been known for a long time to modify kinetochore proteins, while more recently, extensive proteomic screens have identified a large number of microtubule- and spindle-associated proteins that are SUMOylated. The aim of this review is to focus on the possible role of SUMOylation in organization of the spindle and kinetochore complexes. We summarize mitotic and microtubule/spindle-associated proteins that have been identified as SUMO conjugates and present examples regarding their regulation by SUMO. Moreover, we discuss the possible contribution of SUMOylation in organization of larger protein assemblies on the spindle, as well as the role of SUMO-targeted ubiquitylation in control of kinetochore assembly and function. Finally, we propose future directions regarding the study of SUMOylation in regulation of spindle organization and examine the potential of SUMO and SUMO-mediated degradation as target for antimitotic-based therapies. Full article

(This article belongs to the Special Issue Molecular Regulation of Mitosis and Its Role in Disease)

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46 pages, 2942 KiB

Open AccessReview

The Centrosome and the Primary Cilium: The Yin and Yang of a Hybrid Organelle

by Vladimir Joukov and Arcangela De Nicolo

Cells 2019, 8(7), 701; https://doi.org/10.3390/cells8070701 - 10 Jul 2019

Cited by 61 | Viewed by 14310

Abstract

Centrosomes and primary cilia are usually considered as distinct organelles, although both are assembled with the same evolutionary conserved, microtubule-based templates, the centrioles. Centrosomes serve as major microtubule- and actin cytoskeleton-organizing centers and are involved in a variety of intracellular processes, whereas primary [...] Read more.

Centrosomes and primary cilia are usually considered as distinct organelles, although both are assembled with the same evolutionary conserved, microtubule-based templates, the centrioles. Centrosomes serve as major microtubule- and actin cytoskeleton-organizing centers and are involved in a variety of intracellular processes, whereas primary cilia receive and transduce environmental signals to elicit cellular and organismal responses. Understanding the functional relationship between centrosomes and primary cilia is important because defects in both structures have been implicated in various diseases, including cancer. Here, we discuss evidence that the animal centrosome evolved, with the transition to complex multicellularity, as a hybrid organelle comprised of the two distinct, but intertwined, structural-functional modules: the centriole/primary cilium module and the pericentriolar material/centrosome module. The evolution of the former module may have been caused by the expanding cellular diversification and intercommunication, whereas that of the latter module may have been driven by the increasing complexity of mitosis and the requirement for maintaining cell polarity, individuation, and adhesion. Through its unique ability to serve both as a plasma membrane-associated primary cilium organizer and a juxtanuclear microtubule-organizing center, the animal centrosome has become an ideal integrator of extracellular and intracellular signals with the cytoskeleton and a switch between the non-cell autonomous and the cell-autonomous signaling modes. In light of this hypothesis, we discuss centrosome dynamics during cell proliferation, migration, and differentiation and propose a model of centrosome-driven microtubule assembly in mitotic and interphase cells. In addition, we outline the evolutionary benefits of the animal centrosome and highlight the hierarchy and modularity of the centrosome biogenesis networks. Full article

(This article belongs to the Special Issue Molecular Regulation of Mitosis and Its Role in Disease)

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13 pages, 1321 KiB

Open AccessFeature PaperReview

The Role of Phosphatases in Nuclear Envelope Disassembly and Reassembly and Their Relevance to Pathologies

by Florentin Huguet, Shane Flynn and Paola Vagnarelli

Cells 2019, 8(7), 687; https://doi.org/10.3390/cells8070687 - 7 Jul 2019

Cited by 16 | Viewed by 5270

Abstract

The role of kinases in the regulation of cell cycle transitions is very well established, however, over the past decade, studies have identified the ever-growing importance of phosphatases in these processes. It is well-known that an intact or otherwise non-deformed nuclear envelope (NE) [...] Read more.

The role of kinases in the regulation of cell cycle transitions is very well established, however, over the past decade, studies have identified the ever-growing importance of phosphatases in these processes. It is well-known that an intact or otherwise non-deformed nuclear envelope (NE) is essential for maintaining healthy cells and any deviation from this can result in pathological conditions. This review aims at assessing the current understanding of how phosphatases contribute to the remodelling of the nuclear envelope during its disassembling and reformation after cell division and how errors in this process may lead to the development of diseases. Full article

(This article belongs to the Special Issue Molecular Regulation of Mitosis and Its Role in Disease)

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15 pages, 1414 KiB

Open AccessReview

Recent Research Advances in Mitosis during Mammalian Gametogenesis

by Jia-Hao Wang, Yan Li, Shou-Long Deng, Yi-Xun Liu, Zheng-Xing Lian and Kun Yu

Cells 2019, 8(6), 567; https://doi.org/10.3390/cells8060567 - 10 Jun 2019

Cited by 8 | Viewed by 7842

Abstract

Mitosis is a highly sophisticated and well-regulated process during the development and differentiation of mammalian gametogenesis. The regulation of mitosis plays an essential role in keeping the formulation in oogenesis and gametogenesis. In the past few years, substantial research progress has been made [...] Read more.

Mitosis is a highly sophisticated and well-regulated process during the development and differentiation of mammalian gametogenesis. The regulation of mitosis plays an essential role in keeping the formulation in oogenesis and gametogenesis. In the past few years, substantial research progress has been made by showing that cyclins/cyclin-dependent kinase (CDK) have roles in the regulation of meiosis. In addition, more functional signaling molecules have been discovered in mitosis. Growing evidence has also indicated that miRNAs influence cell cycling. In this review, we focus on specific genes, cyclins/Cdk, signaling pathways/molecules, and miRNAs to discuss the latest achievements in understanding their roles in mitosis during gametogenesis. Further elucidation of mitosis during gametogenesis may facilitate delineating all processes of mammalian reproduction and the development of disease treatments. Full article

(This article belongs to the Special Issue Molecular Regulation of Mitosis and Its Role in Disease)

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15 pages, 1100 KiB

Open AccessReview

Recent Progress on the Localization of the Spindle Assembly Checkpoint Machinery to Kinetochores

by Zhen Dou, Diogjena Katerina Prifti, Ping Gui, Xing Liu, Sabine Elowe and Xuebiao Yao

Cells 2019, 8(3), 278; https://doi.org/10.3390/cells8030278 - 23 Mar 2019

Cited by 28 | Viewed by 9271

Abstract

Faithful chromosome segregation during mitosis is crucial for maintaining genome stability. The spindle assembly checkpoint (SAC) is a surveillance mechanism that ensures accurate mitotic progression. Defective SAC signaling leads to premature sister chromatid separation and aneuploid daughter cells. Mechanistically, the SAC couples the [...] Read more.

Faithful chromosome segregation during mitosis is crucial for maintaining genome stability. The spindle assembly checkpoint (SAC) is a surveillance mechanism that ensures accurate mitotic progression. Defective SAC signaling leads to premature sister chromatid separation and aneuploid daughter cells. Mechanistically, the SAC couples the kinetochore microtubule attachment status to the cell cycle progression machinery. In the presence of abnormal kinetochore microtubule attachments, the SAC prevents the metaphase-to-anaphase transition through a complex kinase-phosphatase signaling cascade which results in the correct balance of SAC components recruited to the kinetochore. The correct kinetochore localization of SAC proteins is a prerequisite for robust SAC signaling and, hence, accurate chromosome segregation. Here, we review recent progresses on the kinetochore recruitment of core SAC factors. Full article

(This article belongs to the Special Issue Molecular Regulation of Mitosis and Its Role in Disease)

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