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      The coordination of nuclear envelope assembly and chromosome segregation in metazoans

      review-article
      a , b , c , a , b , c
      Nucleus
      Taylor & Francis
      nuclear envelope, nuclear pore complex, mitosis, chromosome segregation, micronucleus

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          ABSTRACT

          The nuclear envelope (NE) is composed of two lipid bilayer membranes that enclose the eukaryotic genome. In interphase, the NE is perforated by thousands of nuclear pore complexes (NPCs), which allow transport in and out of the nucleus. During mitosis in metazoans, the NE is broken down and then reassembled in a manner that enables proper chromosome segregation and the formation of a single nucleus in each daughter cell. Defects in coordinating NE reformation and chromosome segregation can cause aberrant nuclear architecture. This includes the formation of micronuclei, which can trigger a catastrophic mutational process commonly observed in cancers called chromothripsis. Here, we discuss the current understanding of the coordination of NE reformation with chromosome segregation during mitotic exit in metazoans. We review differing models in the field and highlight recent work suggesting that normal NE reformation and chromosome segregation are physically linked through the timing of mitotic spindle disassembly.

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          The spindle-assembly checkpoint in space and time.

          In eukaryotes, the spindle-assembly checkpoint (SAC) is a ubiquitous safety device that ensures the fidelity of chromosome segregation in mitosis. The SAC prevents chromosome mis-segregation and aneuploidy, and its dysfunction is implicated in tumorigenesis. Recent molecular analyses have begun to shed light on the complex interaction of the checkpoint proteins with kinetochores--structures that mediate the binding of spindle microtubules to chromosomes in mitosis. These studies are finally starting to reveal the mechanisms of checkpoint activation and silencing during mitotic progression.
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            The endoplasmic reticulum: structure, function and response to cellular signaling

            The endoplasmic reticulum (ER) is a large, dynamic structure that serves many roles in the cell including calcium storage, protein synthesis and lipid metabolism. The diverse functions of the ER are performed by distinct domains; consisting of tubules, sheets and the nuclear envelope. Several proteins that contribute to the overall architecture and dynamics of the ER have been identified, but many questions remain as to how the ER changes shape in response to cellular cues, cell type, cell cycle state and during development of the organism. Here we discuss what is known about the dynamics of the ER, what questions remain, and how coordinated responses add to the layers of regulation in this dynamic organelle.
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              Molecular mechanisms of micronucleus, nucleoplasmic bridge and nuclear bud formation in mammalian and human cells.

              Micronuclei (MN) and other nuclear anomalies such as nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) are biomarkers of genotoxic events and chromosomal instability. These genome damage events can be measured simultaneously in the cytokinesis-block micronucleus cytome (CBMNcyt) assay. The molecular mechanisms leading to these events have been investigated over the past two decades using molecular probes and genetically engineered cells. In this brief review, we summarise the wealth of knowledge currently available that best explains the formation of these important nuclear anomalies that are commonly seen in cancer and are indicative of genome damage events that could increase the risk of developmental and degenerative diseases. MN can originate during anaphase from lagging acentric chromosome or chromatid fragments caused by misrepair of DNA breaks or unrepaired DNA breaks. Malsegregation of whole chromosomes at anaphase may also lead to MN formation as a result of hypomethylation of repeat sequences in centromeric and pericentromeric DNA, defects in kinetochore proteins or assembly, dysfunctional spindle and defective anaphase checkpoint genes. NPB originate from dicentric chromosomes, which may occur due to misrepair of DNA breaks, telomere end fusions, and could also be observed when defective separation of sister chromatids at anaphase occurs due to failure of decatenation. NBUD represent the process of elimination of amplified DNA, DNA repair complexes and possibly excess chromosomes from aneuploid cells.
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                Author and article information

                Journal
                Nucleus
                Nucleus
                KNCL
                kncl20
                Nucleus
                Taylor & Francis
                1949-1034
                1949-1042
                2020
                25 March 2020
                25 March 2020
                : 11
                : 1
                : 35-52
                Affiliations
                [a ]Howard Hughes Medical Institute , Chevy Chase, MD, USA
                [b ]Department of Cell Biology, Harvard Medical School , Boston, MA, USA
                [c ]Department of Pediatric Oncology, Dana-Farber Cancer Institute , Boston, MA, USA
                Author notes
                CONTACT David Pellman David_Pellman@ 123456dfci.harvard.edu Howard Hughes Medical Institute , Chevy Chase, MD, USA
                Article
                1742064
                10.1080/19491034.2020.1742064
                7289584
                32208955
                a5e6c7d7-fabc-41b8-bb36-81b44a915164
                © 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 November 2019
                : 8 March 2020
                : 10 March 2020
                Page count
                Figures: 3, References: 131, Pages: 18
                Funding
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: R37 GM061345
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: GM083299
                This work was supported by the Howard Hughes Medical Institute; Lustgarten Foundation; National Institutes of Health [R37 GM061345]; National Institutes of Health [GM083299].
                Categories
                Review

                Molecular biology
                nuclear envelope,nuclear pore complex,mitosis,chromosome segregation,micronucleus

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