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The Journal of Cell Biology May 2023Enduring chromosome segregation errors represent potential threats to genomic stability due to eventual chromosome copy number alterations (aneuploidy) and formation of... (Review)
Review
Enduring chromosome segregation errors represent potential threats to genomic stability due to eventual chromosome copy number alterations (aneuploidy) and formation of micronuclei-key intermediates of a rapid mutational process known as chromothripsis that is found in cancer and congenital disorders. The spindle assembly checkpoint (SAC) has been viewed as the sole surveillance mechanism that prevents chromosome segregation errors during mitosis and meiosis. However, different types of chromosome segregation errors stemming from incorrect kinetochore-microtubule attachments satisfy the SAC and are more frequent than previously anticipated. Remarkably, recent works have unveiled that most of these errors are corrected during anaphase and only rarely result in aneuploidy or formation of micronuclei. Here, we discuss recent progress in our understanding of the origin and fate of chromosome segregation errors that satisfy the SAC and shed light on the surveillance, correction, and clearance mechanisms that prevent their transmission, to preserve genomic stability.
Topics: Humans; Anaphase; Aneuploidy; Chromosome Segregation; Kinetochores; Microtubules; Mitosis; Spindle Apparatus; Genomic Instability
PubMed: 37017932
DOI: 10.1083/jcb.202301106 -
Molecular Cell May 2023Cell cycle and metabolism are intimately intertwined, but how metabolites directly regulate cell-cycle machinery remains elusive. Liu et al. reveal that glycolysis...
Cell cycle and metabolism are intimately intertwined, but how metabolites directly regulate cell-cycle machinery remains elusive. Liu et al. reveal that glycolysis end-product lactate directly binds and inhibits the SUMO protease SENP1 to govern the E3 ligase activity of the anaphase-promoting complex, leading to efficient mitotic exit in proliferative cells.
Topics: Anaphase; Lactic Acid; Mitosis; Anaphase-Promoting Complex-Cyclosome; Cell Cycle Proteins
PubMed: 37207623
DOI: 10.1016/j.molcel.2023.04.013 -
Cells Apr 2022A conserved feature of virtually all higher eukaryotes is that the centromeres are embedded in heterochromatin. Here we provide evidence that this tight association... (Review)
Review
A conserved feature of virtually all higher eukaryotes is that the centromeres are embedded in heterochromatin. Here we provide evidence that this tight association between pericentric heterochromatin and the centromere is essential for proper metaphase exit and progression into telophase. Analysis of chromosome rearrangements that separate pericentric heterochromatin and centromeres indicates that they must remain associated in order to balance Cohesin/DNA catenation-based binding forces and centromere-based pulling forces during the metaphase-anaphase transition. In addition, a centromere embedded in heterochromatin facilitates nuclear envelope assembly around the entire complement of segregating chromosomes. Because the nuclear envelope initially forms on pericentric heterochromatin, nuclear envelope formation proceeds from the pole, thus providing time for incorporation of lagging and trailing chromosome arms into the newly formed nucleus. Additional analysis of noncanonical mitoses provides further insights into the functional significance of the tight association between heterochromatin and centromeres.
Topics: Anaphase; Centromere; Heterochromatin; Metaphase; Mitosis
PubMed: 35406810
DOI: 10.3390/cells11071247 -
Seminars in Cell & Developmental Biology Sep 2021Mitotic cell divisions ensure stable transmission of genetic information from a mother to daughter cells in a series of generations. To ensure this crucial task is... (Review)
Review
Mitotic cell divisions ensure stable transmission of genetic information from a mother to daughter cells in a series of generations. To ensure this crucial task is accomplished, the cell forms a bipolar structure called the mitotic spindle that divides sister chromatids to the opposite sides of the dividing mother cell. After successful establishment of stable attachments of microtubules to chromosomes and inspection of connections between them, at the heart of mitosis, the cell starts the process of segregation. This spectacular moment in the life of a cell is termed anaphase, and it involves two distinct processes: depolymerization of microtubules bound to chromosomes, which is also known as anaphase A, and elongation of the spindle or anaphase B. Both processes ensure physical separation of disjointed sister chromatids. In this chapter, we review the mechanisms of anaphase B spindle elongation primarily in mammalian systems, combining different pioneering ideas and concepts with more recent findings that shed new light on the force generation and regulation of biochemical modules operating during spindle elongation. Finally, we present a comprehensive model of spindle elongation that includes structural, biophysical, and molecular aspects of anaphase B.
Topics: Anaphase; Chromosome Segregation; Humans; Microtubules
PubMed: 33849764
DOI: 10.1016/j.semcdb.2021.03.023 -
Nature Structural & Molecular Biology Sep 2023SUMOylation regulates numerous cellular processes, but what represents the essential functions of this protein modification remains unclear. To address this, we...
SUMOylation regulates numerous cellular processes, but what represents the essential functions of this protein modification remains unclear. To address this, we performed genome-scale CRISPR-Cas9-based screens, revealing that the BLM-TOP3A-RMI1-RMI2 (BTRR)-PICH pathway, which resolves ultrafine anaphase DNA bridges (UFBs) arising from catenated DNA structures, and the poorly characterized protein NIP45/NFATC2IP become indispensable for cell proliferation when SUMOylation is inhibited. We demonstrate that NIP45 and SUMOylation orchestrate an interphase pathway for converting DNA catenanes into double-strand breaks (DSBs) that activate the G2 DNA-damage checkpoint, thereby preventing cytokinesis failure and binucleation when BTRR-PICH-dependent UFB resolution is defective. NIP45 mediates this new TOP2-independent DNA catenane resolution process via its SUMO-like domains, promoting SUMOylation of specific factors including the SLX4 multi-nuclease complex, which contributes to catenane conversion into DSBs. Our findings establish that SUMOylation exerts its essential role in cell proliferation by enabling resolution of toxic DNA catenanes via nonepistatic NIP45- and BTRR-PICH-dependent pathways to prevent mitotic failure.
Topics: DNA, Catenated; Anaphase; DNA; Sumoylation
PubMed: 37474739
DOI: 10.1038/s41594-023-01045-0 -
F1000Research 2019The separation of sister chromatids at anaphase, which is regulated by an E3 ubiquitin ligase called the anaphase-promoting complex/cyclosome (APC/C), is arguably the... (Review)
Review
The separation of sister chromatids at anaphase, which is regulated by an E3 ubiquitin ligase called the anaphase-promoting complex/cyclosome (APC/C), is arguably the most important irrevocable event during the cell cycle. The APC/C and cyclin-dependent kinase 1 (Cdk1) are just two of the many significant cell cycle regulators and exert control through ubiquitylation and phosphorylation, respectively. The temporal and spatial regulation of the APC/C is achieved by multiple mechanisms, including phosphorylation, interaction with the structurally related co-activators Cdc20 and Cdh1, loading of distinct E2 ubiquitin-conjugating enzymes, binding with inhibitors and differential affinities for various substrates. Since the discovery of APC/C 25 years ago, intensive studies have uncovered many aspects of APC/C regulation, but we are still far from a full understanding of this important cellular machinery. Recent high-resolution cryogenic electron microscopy analysis and reconstitution of the APC/C have greatly advanced our understanding of molecular mechanisms underpinning the enzymatic properties of APC/C. In this review, we will examine the historical background and current understanding of APC/C regulation.
Topics: Anaphase; Anaphase-Promoting Complex-Cyclosome; Animals; Cdc20 Proteins; Cdh1 Proteins; Humans; Saccharomycetales; Xenopus
PubMed: 31164978
DOI: 10.12688/f1000research.18582.1 -
The Journal of Cell Biology Feb 2008Aneuploidy and chromosome instability (CIN) are hallmarks of the majority of solid tumors, but the relationship between them is not well understood. In this issue,... (Review)
Review
Aneuploidy and chromosome instability (CIN) are hallmarks of the majority of solid tumors, but the relationship between them is not well understood. In this issue, Thompson and Compton (Thompson, S.L., and D.A. Compton. 2008. Examining the link between chromosomal instability and aneuploidy in human cells. J. Cell. Biol. 180:665-672) investigate the mechanism of CIN in cancer cells and find that CIN arises primarily from defective kinetochore-spindle attachments that evade detection by the spindle checkpoint and persist into anaphase. They also explore the consequences of artificially elevating chromosome missegregation in otherwise karyotypically normal cells. Their finding that induced aneuploidy is rapidly selected against suggests that the persistence of aneuploid cells in tumors requires not only chromosome missegregation but also additional, as yet poorly defined events.
Topics: Anaphase; Aneuploidy; Animals; Cell Transformation, Neoplastic; Chromosomal Instability; Chromosome Segregation; Genes, cdc; Humans; Kinetochores; Neoplasms; Spindle Apparatus
PubMed: 18283117
DOI: 10.1083/jcb.200801030 -
International Journal of Molecular... Jul 2017Aneuploidy is a leading genetic cause of birth defects and lower implantation rates in humans. Most errors in chromosome number originate from oocytes. Aneuploidy in... (Review)
Review
Aneuploidy is a leading genetic cause of birth defects and lower implantation rates in humans. Most errors in chromosome number originate from oocytes. Aneuploidy in oocytes increases with advanced maternal age. Recent studies support the hypothesis that cohesion deterioration with advanced maternal age represents a leading cause of age-related aneuploidy. Cohesin generates cohesion, and is established only during the premeiotic S phase of fetal development without any replenishment throughout a female's period of fertility. Cohesion holds sister chromatids together until meiosis resumes at puberty, and then chromosome segregation requires the release of sister chromatid cohesion from chromosome arms and centromeres at anaphase I and anaphase II, respectively. The time of cohesion cleavage plays an important role in correct chromosome segregation. This review focuses specifically on the causes and effects of age-related cohesion deterioration in female meiosis.
Topics: Aging; Anaphase; Aneuploidy; Animals; Chromatids; Chromosome Segregation; Chromosomes, Human; Female; Humans; Male; Oocytes
PubMed: 28737671
DOI: 10.3390/ijms18071578 -
Current Biology : CB May 2021During metaphase, chromosomes are aligned in a lineup at the equatorial plane of the spindle to ensure synchronous poleward movement of chromatids in anaphase and proper... (Review)
Review
During metaphase, chromosomes are aligned in a lineup at the equatorial plane of the spindle to ensure synchronous poleward movement of chromatids in anaphase and proper nuclear reformation at the end of mitosis. Chromosome alignment relies on microtubules, several types of motor protein and numerous other microtubule-associated and regulatory proteins. Because of the multitude of players involved, the mechanisms of chromosome alignment are still under debate. Here, we discuss the current models of alignment based on poleward pulling forces exerted onto sister kinetochores by kinetochore microtubules, which show length-dependent dynamics and undergo poleward flux, and polar ejection forces that push the chromosome arms away from the pole. We link these models with the recent ideas based on mechanical coupling between bridging and kinetochore microtubules, where sliding of bridging microtubules promotes overlap length-dependent sliding of kinetochore fibers and thus the alignment of sister kinetochores at the spindle equator. Finally, we discuss theoretical models of forces acting on chromosomes during metaphase.
Topics: Anaphase; Biomechanical Phenomena; Chromosomes; Kinetochores; Metaphase; Microtubules; Mitosis; Spindle Apparatus
PubMed: 34033791
DOI: 10.1016/j.cub.2021.03.082 -
Cellular and Molecular Life Sciences :... Jul 2010The mitotic spindle uses dynamic microtubules and mitotic motors to generate the pico-Newton scale forces that are needed to drive the mitotic movements that underlie... (Review)
Review
The mitotic spindle uses dynamic microtubules and mitotic motors to generate the pico-Newton scale forces that are needed to drive the mitotic movements that underlie chromosome capture, alignment and segregation. Here, we consider the biophysical and molecular basis of force-generation for chromosome movements in the spindle, and, with reference to the Drosophila embryo mitotic spindle, we briefly discuss how mathematical modeling can complement experimental analysis to illuminate the mechanisms of chromosome-to-pole motility during anaphase A and spindle elongation during anaphase B.
Topics: Anaphase; Animals; Chromosome Segregation; Drosophila; Microtubules; Mitosis; Models, Theoretical; Molecular Motor Proteins; Spindle Apparatus
PubMed: 20221784
DOI: 10.1007/s00018-010-0326-6