Special Issue "Chromosome Segregation Defects in the Origin of Genomic Instability"

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (30 November 2019).

Special Issue Editor

Dr. Félix Machín
Website
Guest Editor
Hospital Universitario Nuestra Senora de Candelaria, Santa Cruz de Tenerife, Spain
Interests: chromosome segregation; cancer; genomic instability; DNA repair; Saccharomyces cerevisiae; chemical genetics

Special Issue Information

Dear Colleagues,

The cell cycle, whose purpose is to become two where there was only one, is extraordinarily complex and tightly regulated. Any error in this process could cause an unsuccessful transmission of genetic material, leading from cancer to birth defects. A key stage during the cell cycle is anaphase, where an army of proteins gradually resolve, separate, and pull the sister chromatids to the daughter cells. Anaphase is particularly concerning as a source of genomic instability, since there are no good options for the cell to correctly deal with chromosome segregation errors (Figure 1).

Figure 1: Outcomes in diploid cells of the breakage and repair of anaphase bridges formed by unresolved sister chromatids (USC). A: The USC bridge just involves one homolog. B: The USC involves both homologs. Broken sisters are segregated symmetrically. C: Like in B but broken sisters are segregated asymmetrically. Further details in "Machín et al. Curr Genet. 2016; 62(1):7-13".

There are several genetically inherited human diseases, especially cancer-prone syndromes, that show chromosome segregation defects at the cellular level. In addition, many carcinogens and, paradoxically, clinically-used antitumor agents have a direct impact on the fidelity of chromosome transmission. Amongst the most common anaphase aberrations, we find chromatin and ultrafine anaphase bridges, lagging chromosomes, the breakage-fusion-bridge cycle, and chromosome nondisjunction. The physical causes of these aberrations include the unnatural presence of underreplicated chromosomes, unresolved recombination intermediates, topological constrains, proteinaceous linkages, multicentric chromosomes, telomere fusions, syntelyc/monotelyc attachments, and polycentrosomy. At a molecular level, mutations in numerous genes cause chromosome segregation defects, including those genes involved in DNA damage and replication checkpoints, the spindle assembly checkpoint, the structural maintenance of chromosomes (SMC) complexes (condensin, cohesin, and Smc5/6), topoisomerase II, DNA repair helicases, and structure-specific endonucleases.

In this Issue, we aim to gather a collection of reviews, research articles, and concept papers about the molecular players involved in the successful segregation of chromosomes, both in mitosis and meiosis, as well as manuscripts dealing with the instability footprints found in the progeny.

Kind regards,

Dr. Félix Machín
Guest Editor

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Keywords

  • genome instability,
  • chromosome segregation
  • mitotic catastrophe
  • anaphase bridges
  • cohesins
  • condensins
  • topoisomerases
  • DNA repair
  • checkpoints
  • mitosis
  • meiosis
  • cancer.

Published Papers (6 papers)

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Research

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Open AccessArticle
MCPH1 Lack of Function Enhances Mitotic Cell Sensitivity Caused by Catalytic Inhibitors of Topo II
Genes 2020, 11(4), 406; https://doi.org/10.3390/genes11040406 - 08 Apr 2020
Abstract
The capacity of Topoisomerase II (Topo II) to remove DNA catenations that arise after replication is essential to ensure faithful chromosome segregation. Topo II activity is monitored during G2 by a specific checkpoint pathway that delays entry into mitosis until the chromosomes are [...] Read more.
The capacity of Topoisomerase II (Topo II) to remove DNA catenations that arise after replication is essential to ensure faithful chromosome segregation. Topo II activity is monitored during G2 by a specific checkpoint pathway that delays entry into mitosis until the chromosomes are properly decatenated. Recently, we demonstrated that the mitotic defects that are characteristic of cells depleted of MCPH1 function, a protein mutated in primary microcephaly, are not a consequence of a weakened G2 decatenation checkpoint response. However, the mitotic defects could be accounted for by a minor defect in the activity of Topo II during G2/M. To test this hypothesis, we have tracked at live single cell resolution the dynamics of mitosis in MCPH1 depleted HeLa cells upon catalytic inhibition of Topo II. Our analyses demonstrate that neither chromosome alignment nor segregation are more susceptible to minor perturbation in decatenation in MCPH1 deficient cells, as compared with control cells. Interestingly, MCPH1 depleted cells were more prone to mitotic cell death when decatenation was perturbed. Furthermore, when the G2 arrest that was induced by catalytic inhibition of Topo II was abrogated by Chk1 inhibition, the incidence of mitotic cell death was also increased. Taken together, our data suggest that the MCPH1 lack of function increases mitotic cell hypersensitivity to the catalytic inhibition of Topo II. Full article
(This article belongs to the Special Issue Chromosome Segregation Defects in the Origin of Genomic Instability)
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Review

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Open AccessReview
CDK Regulation of Meiosis: Lessons from S. cerevisiae and S. pombe
Genes 2020, 11(7), 723; https://doi.org/10.3390/genes11070723 - 29 Jun 2020
Abstract
Meiotic progression requires precise orchestration, such that one round of DNA replication is followed by two meiotic divisions. The order and timing of meiotic events is controlled through the modulation of the phosphorylation state of proteins. Key components of this phospho-regulatory system include [...] Read more.
Meiotic progression requires precise orchestration, such that one round of DNA replication is followed by two meiotic divisions. The order and timing of meiotic events is controlled through the modulation of the phosphorylation state of proteins. Key components of this phospho-regulatory system include cyclin-dependent kinase (CDK) and its cyclin regulatory subunits. Over the past two decades, studies in budding and fission yeast have greatly informed our understanding of the role of CDK in meiotic regulation. In this review, we provide an overview of how CDK controls meiotic events in both budding and fission yeast. We discuss mechanisms of CDK regulation through post-translational modifications and changes in the levels of cyclins. Finally, we highlight the similarities and differences in CDK regulation between the two yeast species. Since CDK and many meiotic regulators are highly conserved, the findings in budding and fission yeasts have revealed conserved mechanisms of meiotic regulation among eukaryotes. Full article
(This article belongs to the Special Issue Chromosome Segregation Defects in the Origin of Genomic Instability)
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Open AccessReview
Working on Genomic Stability: From the S-Phase to Mitosis
Genes 2020, 11(2), 225; https://doi.org/10.3390/genes11020225 - 20 Feb 2020
Cited by 2
Abstract
Fidelity in chromosome duplication and segregation is indispensable for maintaining genomic stability and the perpetuation of life. Challenges to genome integrity jeopardize cell survival and are at the root of different types of pathologies, such as cancer. The following three main sources of [...] Read more.
Fidelity in chromosome duplication and segregation is indispensable for maintaining genomic stability and the perpetuation of life. Challenges to genome integrity jeopardize cell survival and are at the root of different types of pathologies, such as cancer. The following three main sources of genomic instability exist: DNA damage, replicative stress, and chromosome segregation defects. In response to these challenges, eukaryotic cells have evolved control mechanisms, also known as checkpoint systems, which sense under-replicated or damaged DNA and activate specialized DNA repair machineries. Cells make use of these checkpoints throughout interphase to shield genome integrity before mitosis. Later on, when the cells enter into mitosis, the spindle assembly checkpoint (SAC) is activated and remains active until the chromosomes are properly attached to the spindle apparatus to ensure an equal segregation among daughter cells. All of these processes are tightly interconnected and under strict regulation in the context of the cell division cycle. The chromosomal instability underlying cancer pathogenesis has recently emerged as a major source for understanding the mitotic processes that helps to safeguard genome integrity. Here, we review the special interconnection between the S-phase and mitosis in the presence of under-replicated DNA regions. Furthermore, we discuss what is known about the DNA damage response activated in mitosis that preserves chromosomal integrity. Full article
(This article belongs to the Special Issue Chromosome Segregation Defects in the Origin of Genomic Instability)
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Open AccessReview
Regulation of Mitotic Exit by Cell Cycle Checkpoints: Lessons From Saccharomyces cerevisiae
Genes 2020, 11(2), 195; https://doi.org/10.3390/genes11020195 - 12 Feb 2020
Abstract
In order to preserve genome integrity and their ploidy, cells must ensure that the duplicated genome has been faithfully replicated and evenly distributed before they complete their division by mitosis. To this end, cells have developed highly elaborated checkpoints that halt mitotic progression [...] Read more.
In order to preserve genome integrity and their ploidy, cells must ensure that the duplicated genome has been faithfully replicated and evenly distributed before they complete their division by mitosis. To this end, cells have developed highly elaborated checkpoints that halt mitotic progression when problems in DNA integrity or chromosome segregation arise, providing them with time to fix these issues before advancing further into the cell cycle. Remarkably, exit from mitosis constitutes a key cell cycle transition that is targeted by the main mitotic checkpoints, despite these surveillance mechanisms being activated by specific intracellular signals and acting at different stages of cell division. Focusing primarily on research carried out using Saccharomyces cerevisiae as a model organism, the aim of this review is to provide a general overview of the molecular mechanisms by which the major cell cycle checkpoints control mitotic exit and to highlight the importance of the proper regulation of this process for the maintenance of genome stability during the distribution of the duplicated chromosomes between the dividing cells. Full article
(This article belongs to the Special Issue Chromosome Segregation Defects in the Origin of Genomic Instability)
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Open AccessReview
Resolvases, Dissolvases, and Helicases in Homologous Recombination: Clearing the Road for Chromosome Segregation
Genes 2020, 11(1), 71; https://doi.org/10.3390/genes11010071 - 08 Jan 2020
Abstract
The execution of recombinational pathways during the repair of certain DNA lesions or in the meiotic program is associated to the formation of joint molecules that physically hold chromosomes together. These structures must be disengaged prior to the onset of chromosome segregation. Failure [...] Read more.
The execution of recombinational pathways during the repair of certain DNA lesions or in the meiotic program is associated to the formation of joint molecules that physically hold chromosomes together. These structures must be disengaged prior to the onset of chromosome segregation. Failure in the resolution of these linkages can lead to chromosome breakage and nondisjunction events that can alter the normal distribution of the genomic material to the progeny. To avoid this situation, cells have developed an arsenal of molecular complexes involving helicases, resolvases, and dissolvases that recognize and eliminate chromosome links. The correct orchestration of these enzymes promotes the timely removal of chromosomal connections ensuring the efficient segregation of the genome during cell division. In this review, we focus on the role of different DNA processing enzymes that collaborate in removing the linkages generated during the activation of the homologous recombination machinery as a consequence of the appearance of DNA breaks during the mitotic and meiotic programs. We will also discuss about the temporal regulation of these factors along the cell cycle, the consequences of their loss of function, and their specific role in the removal of chromosomal links to ensure the accurate segregation of the genomic material during cell division. Full article
(This article belongs to the Special Issue Chromosome Segregation Defects in the Origin of Genomic Instability)
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Open AccessReview
Common Features of the Pericentromere and Nucleolus
Genes 2019, 10(12), 1029; https://doi.org/10.3390/genes10121029 - 10 Dec 2019
Cited by 2
Abstract
Both the pericentromere and the nucleolus have unique characteristics that distinguish them amongst the rest of genome. Looping of pericentromeric DNA, due to structural maintenance of chromosome (SMC) proteins condensin and cohesin, drives its ability to maintain tension during metaphase. Similar loops are [...] Read more.
Both the pericentromere and the nucleolus have unique characteristics that distinguish them amongst the rest of genome. Looping of pericentromeric DNA, due to structural maintenance of chromosome (SMC) proteins condensin and cohesin, drives its ability to maintain tension during metaphase. Similar loops are formed via condensin and cohesin in nucleolar ribosomal DNA (rDNA). Condensin and cohesin are also concentrated in transfer RNA (tRNA) genes, genes which may be located within the pericentromere as well as tethered to the nucleolus. Replication fork stalling, as well as downstream consequences such as genomic recombination, are characteristic of both the pericentromere and rDNA. Furthermore, emerging evidence suggests that the pericentromere may function as a liquid–liquid phase separated domain, similar to the nucleolus. We therefore propose that the pericentromere and nucleolus, in part due to their enrichment of SMC proteins and others, contain similar domains that drive important cellular activities such as segregation, stability, and repair. Full article
(This article belongs to the Special Issue Chromosome Segregation Defects in the Origin of Genomic Instability)
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