Genes

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14 pages, 2607 KiB

Open AccessArticle

MCPH1 Lack of Function Enhances Mitotic Cell Sensitivity Caused by Catalytic Inhibitors of Topo II

by María Arroyo, Antonio Sánchez, Ana Cañuelo, Rosalía F. Heredia-Molina, Eduardo Martínez-Molina, Duncan J. Clarke and Juan Alberto Marchal

Genes 2020, 11(4), 406; https://doi.org/10.3390/genes11040406 - 8 Apr 2020

Viewed by 2950

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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29 pages, 2254 KiB

Open AccessReview

Anaphase Bridges: Not All Natural Fibers Are Healthy

by Alice Finardi, Lucia F. Massari and Rosella Visintin

Genes 2020, 11(8), 902; https://doi.org/10.3390/genes11080902 - 7 Aug 2020

Cited by 18 | Viewed by 7147

Abstract

At each round of cell division, the DNA must be correctly duplicated and distributed between the two daughter cells to maintain genome identity. In order to achieve proper chromosome replication and segregation, sister chromatids must be recognized as such and kept together until [...] Read more.

At each round of cell division, the DNA must be correctly duplicated and distributed between the two daughter cells to maintain genome identity. In order to achieve proper chromosome replication and segregation, sister chromatids must be recognized as such and kept together until their separation. This process of cohesion is mainly achieved through proteinaceous linkages of cohesin complexes, which are loaded on the sister chromatids as they are generated during S phase. Cohesion between sister chromatids must be fully removed at anaphase to allow chromosome segregation. Other (non-proteinaceous) sources of cohesion between sister chromatids consist of DNA linkages or sister chromatid intertwines. DNA linkages are a natural consequence of DNA replication, but must be timely resolved before chromosome segregation to avoid the arising of DNA lesions and genome instability, a hallmark of cancer development. As complete resolution of sister chromatid intertwines only occurs during chromosome segregation, it is not clear whether DNA linkages that persist in mitosis are simply an unwanted leftover or whether they have a functional role. In this review, we provide an overview of DNA linkages between sister chromatids, from their origin to their resolution, and we discuss the consequences of a failure in their detection and processing and speculate on their potential role. Full article

(This article belongs to the Special Issue Chromosome Segregation Defects in the Origin of Genomic Instability)

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27 pages, 1923 KiB

Open AccessReview

CDK Regulation of Meiosis: Lessons from S. cerevisiae and S. pombe

by Anne M. MacKenzie and Soni Lacefield

Genes 2020, 11(7), 723; https://doi.org/10.3390/genes11070723 - 29 Jun 2020

Cited by 19 | Viewed by 9979

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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28 pages, 868 KiB

Open AccessReview

Working on Genomic Stability: From the S-Phase to Mitosis

by Sara Ovejero, Avelino Bueno and María P. Sacristán

Genes 2020, 11(2), 225; https://doi.org/10.3390/genes11020225 - 20 Feb 2020

Cited by 31 | Viewed by 7638

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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17 pages, 542 KiB

Open AccessReview

Regulation of Mitotic Exit by Cell Cycle Checkpoints: Lessons From Saccharomyces cerevisiae

by Laura Matellán and Fernando Monje-Casas

Genes 2020, 11(2), 195; https://doi.org/10.3390/genes11020195 - 12 Feb 2020

Cited by 20 | Viewed by 6688

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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22 pages, 1415 KiB

Open AccessReview

Resolvases, Dissolvases, and Helicases in Homologous Recombination: Clearing the Road for Chromosome Segregation

by Pedro A. San-Segundo and Andrés Clemente-Blanco

Genes 2020, 11(1), 71; https://doi.org/10.3390/genes11010071 - 8 Jan 2020

Cited by 12 | Viewed by 4891

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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17 pages, 731 KiB

Open AccessReview

Common Features of the Pericentromere and Nucleolus

by Colleen J. Lawrimore and Kerry Bloom

Genes 2019, 10(12), 1029; https://doi.org/10.3390/genes10121029 - 10 Dec 2019

Cited by 16 | Viewed by 5845

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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Other

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31 pages, 5792 KiB

Open AccessConcept Paper

Implications of Metastable Nicks and Nicked Holliday Junctions in Processing Joint Molecules in Mitosis and Meiosis

by Félix Machín

Genes 2020, 11(12), 1498; https://doi.org/10.3390/genes11121498 - 12 Dec 2020

Cited by 6 | Viewed by 2793

Abstract

Joint molecules (JMs) are intermediates of homologous recombination (HR). JMs rejoin sister or homolog chromosomes and must be removed timely to allow segregation in anaphase. Current models pinpoint Holliday junctions (HJs) as a central JM. The canonical HJ (cHJ) is a four-way DNA [...] Read more.

Joint molecules (JMs) are intermediates of homologous recombination (HR). JMs rejoin sister or homolog chromosomes and must be removed timely to allow segregation in anaphase. Current models pinpoint Holliday junctions (HJs) as a central JM. The canonical HJ (cHJ) is a four-way DNA that needs specialized nucleases, a.k.a. resolvases, to resolve into two DNA molecules. Alternatively, a helicase–topoisomerase complex can deal with pairs of cHJs in the dissolution pathway. Aside from cHJs, HJs with a nick at the junction (nicked HJ; nHJ) can be found in vivo and are extremely good substrates for resolvases in vitro. Despite these findings, nHJs have been neglected as intermediates in HR models. Here, I present a conceptual study on the implications of nicks and nHJs in the final steps of HR. I address this from a biophysical, biochemical, topological, and genetic point of view. My conclusion is that they ease the elimination of JMs while giving genetic directionality to the final products. Additionally, I present an alternative view of the dissolution pathway since the nHJ that results from the second end capture predicts a cross-join isomerization. Finally, I propose that this isomerization nicely explains the strict crossover preference observed in synaptonemal-stabilized JMs in meiosis. Full article

(This article belongs to the Special Issue Chromosome Segregation Defects in the Origin of Genomic Instability)

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