Chromosome mis-segregation and cytokinesis failure in trisomic human cells

Nicholson, Joshua M.; Macedo, Joana Catarina; Mattingly, Aaron; Wangsa, Darawalee; Camps, Jordi; Lima, Vera; Gomes, Ana Margarida; Dória, Sofia; Ried, Thomas; Logarinho, Elsa; Cimini, Daniela

doi:10.7554/elife.05068

Cited by 95 publications

(99 citation statements)

References 74 publications

(125 reference statements)

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“…Whereas numerical CIN, also known as aneuploidy, is characterized by a gain or loss of whole chromosomes that leads to a change in a cell karyotype (Tanaka and Hirota 2016). Defects underlying CIN include lagging chromosomes (Ricke et al 2008), micronuclei (He et al 2019), chromatin bridges (Passerini et al 2016), chromosome missegregation, cytokinesis failure (Fujiwara et al 2005; Nicholson et al 2015), telomere dysfunction (Gisselsson et al 2001) and spindle failure (Maiato and Logarinho 2014; Vitre et al 2015). Approaches to evaluate aneuploidy and examine defects underlying CIN remain critical in the study of cancer biology.…”

Section: Methods Of Detection and Analysis For Genomic Instability In...mentioning

confidence: 99%

Tools used to assay genomic instability in cancers and cancer meiomitosis

Gantchev

Ramchatesingh

Berman-Rosa

et al. 2021

J. Cell Commun. Signal.

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Genomic instability is a defining characteristic of cancer and the analysis of DNA damage at the chromosome level is a crucial part of the study of carcinogenesis and genotoxicity. Chromosomal instability (CIN), the most common level of genomic instability in cancers, is defined as the rate of loss or gain of chromosomes through successive divisions. As such, DNA in cancer cells is highly unstable. However, the underlying mechanisms remain elusive. There is a debate as to whether instability succeeds transformation, or if it is a by‐product of cancer, and therefore, studying potential molecular and cellular contributors of genomic instability is of high importance. Recent work has suggested an important role for ectopic expression of meiosis genes in driving genomic instability via a process called meiomitosis. Improving understanding of these mechanisms can contribute to the development of targeted therapies that exploit DNA damage and repair mechanisms. Here, we discuss a workflow of novel and established techniques used to assess chromosomal instability as well as the nature of genomic instability such as double strand breaks, micronuclei, and chromatin bridges. For each technique, we discuss their advantages and limitations in a lab setting. Lastly, we provide detailed protocols for the discussed techniques.

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“…Chromosomal numbers were counted as previous reported (Nicholson et al 2015) with minor modifications. Briefly, cell cultures were incubated in 1000 ng/mL Colcemid (Karyomax, Invitrogen) for 3-6 h at 37°C to enrich in mitotically arrested cells.…”

Section: Tissue Harvesting and Cell Culturementioning

confidence: 99%

Natural antisense transcript of Period2, Per2AS, regulates the amplitude of the mouse circadian clock

et al. 2021

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In mammals, a set of core clock genes form transcription–translation feedback loops to generate circadian oscillations. We and others recently identified a novel transcript at the Period2 (Per2) locus that is transcribed from the antisense strand of Per2. This transcript, Per2AS, is expressed rhythmically and antiphasic to Per2 mRNA, leading to our hypothesis that Per2AS and Per2 mutually inhibit each other's expression and form a double negative feedback loop. By perturbing the expression of Per2AS, we found that Per2AS transcription, but not transcript, represses Per2. However, Per2 does not repress Per2AS, as Per2 knockdown led to a decrease in the Per2AS level, indicating that Per2AS forms a single negative feedback loop with Per2 and maintains the level of Per2 within the oscillatory range. Per2AS also regulates the amplitude of the circadian clock, and this function cannot be solely explained through its interaction with Per2, as Per2 knockdown does not recapitulate the phenotypes of Per2AS perturbation. Overall, our data indicate that Per2AS is an important regulatory molecule in the mammalian circadian clock machinery. Our work also supports the idea that antisense transcripts of core clock genes constitute a common feature of circadian clocks, as they are found in other organisms.

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“…The discrepancy could be attributed to differences in cell types or in the detection methods used. A recent study directly analyzed the frequency of anaphase lagging chromosomes in aneuploid and diploid cells (Nicholson et al, 2015). In the colorectal cancer cell line DLD-1, trisomy 7 or 13 cells were found to display higher frequencies of anaphase lagging chromosomes compared to the parental diploid cells.…”

Section: Aneuploidy-associated Stressmentioning

confidence: 99%

Cellular Stress Associated with Aneuploidy

et al. 2018

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Aneuploidy, chromosome stoichiometry that deviates from exact multiples of the haploid compliment of an organism, exists in eukaryotic microbes, several normal human tissues, and the majority of solid tumors. Here, we review the current understanding about the cellular stress states that may result from aneuploidy. The topics of aneuploidy-induced proteotoxic, metabolic, replication, and mitotic stress are assessed in the context of the gene dosage imbalance observed in aneuploid cells. We also highlight emerging findings related to the downstream effects of aneuploidy-induced cellular stress on the immune surveillance against aneuploid cells.

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“…Chromosomal number was counted as previous reported (Nicholson et al 2015) with minor modifications. Briefly, cell cultures were incubated in 1000 ng/ml Colcemid (Karyomax, Invitrogen) at 37°C for 3-6 hr to enrich in mitotically arrested cells.…”

Section: Nih3t3 Hek293/t17 Mouse Embryonic Fibroblasts (Mefs) Per2mentioning

confidence: 99%

Natural Antisense Transcript ofPeriod2, Per2AS, regulates the amplitude of the mouse circadian clock

Mosig

Castaneda

Deslauriers

et al. 2020

Preprint

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Circadian transcriptome studies identified a novel transcript at the Period2 (Per2) locus, which we named Per2AS. Per2AS is a long non-coding RNA transcribed from the antisense strand of Per2, and is expressed rhythmically and anti-phasic to Per2 mRNA. Previously, we mathematically tested the hypothesis that Per2AS and Per2 mutually inhibit each other’s expression by forming a double negative feedback loop, and found that Per2AS expands the oscillatory domain. In this study, we have experimentally tested this prediction by perturbing the expression of Per2AS in mouse fibroblasts. We found that Per2AS represses Per2 pre-transcriptionally in cis and regulates the amplitude of the circadian clock, but not period or phase. Unexpectedly, we also found that Per2 positively regulates Per2AS post-transcriptionally, indicating that Per2AS and Per2 form a single negative feedback loop. Because knock-down of Per2 does not recapitulate the phenotypes of Per2AS perturbation and Per2AS also activates Bmal1 in trans, we propose that Per2AS regulates the amplitude of the circadian clock without producing a protein by rewiring the molecular clock circuit.

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“…It is important to keep in mind, that when one quantifies chromosome mis-segregation frequencies in tissue culture cells, most cell lines already exhibit low levels of chromosome missegregation, even in the absence of CIN-inducing mutations. [5,17,18,23,70] These mis-segregation events will lead to karyotype heterogeneity and karyotype evolution in the cell population and might explain the low rate of aneuploidy and karyotype evolution in cell cultures in which no (additional) CIN is induced (see Figure 2a for an example of karyotype evolution with low CIN). However, whether this "low-grade background" CIN rate is representative for the in vivo situation still needs to be assessed.…”

Section: Cin Can Have Highly Differential Effects On Cellsmentioning

confidence: 99%

“…[14][15][16][17][18] In vitro CIN measurements can also be used to characterize animal models. For instance, some studies make use of mouse embryonic fibroblasts (MEFs) from mouse models of genetically induced CIN to estimate the in vivo rate of CIN.…”

Section: How and Why Is Cin Measured In Vitro?mentioning

confidence: 99%

“…[17,18] A trisomy of chromosome 13 in human cells can lead to failing cytokinesis, while a trisomy of chromosome 7 does not, showing that different aneuploid karyotypes can cause different forms of CIN. [17] However, in fully triploid fibroblasts (three copies of each chromosome) the percentage of aneuploid cells increases, but the rate of chromosome mis-segregation (CIN), relative to a euploid control, does not. [6] This can be explained by the fact that triploid cells that encountered chromosome losses had a growth advantage relative to their fully triploid counterparts, whereas chromosome losses were selected against in the diploid cells; this shows that the increased rate of aneuploidy was due to selection, not an increased CIN rate.…”

Section: Does Aneuploidy Lead To Cin?mentioning

confidence: 99%

“…The effects of CIN have been found to be strongly dependent on the rate and type of chromosome mis-segregation or mitotic defect. [14][15][16][17][18] CIN is often measured in a tissue culture setting, which we, for the purpose of this review, define as in vitro. CIN can be quantified via time-lapse microscopy or immunofluorescence staining of fixed cells in mitosis.…”

Section: How and Why Is Cin Measured In Vitro?mentioning

confidence: 99%

“…[40,41] Indeed, several trisomies, tetrasomies, and a few doubletrisomies were shown to cause further mis-segregation events in both cancer and non-cancer cell lines. [17,18] A trisomy of chromosome 13 in human cells can lead to failing cytokinesis, while a trisomy of chromosome 7 does not, showing that different aneuploid karyotypes can cause different forms of CIN. [17] However, in fully triploid fibroblasts (three copies of each chromosome) the percentage of aneuploid cells increases, but the rate of chromosome mis-segregation (CIN), relative to a euploid control, does not.…”

Section: Does Aneuploidy Lead To Cin?mentioning

confidence: 99%

“…[5,17,18,23,70] These mis-segregation events will lead to karyotype heterogeneity and karyotype evolution in the cell population and might explain the low rate of aneuploidy and karyotype evolution in cell cultures in which no (additional) CIN is induced (see Figure 2a for an example of karyotype evolution with low CIN). However, whether this "low-grade background" CIN rate is representative for the in vivo situation still needs to be assessed.…”

Section: Cin Can Have Highly Differential Effects On Cellsmentioning

confidence: 99%

“…CIN is most often measured in vitro, for instance when assessing the effects of overexpression or inhibition of proteins or the effects of drugs. [14][15][16][17][18] In vitro CIN measurements can also be used to characterize animal models. For instance, some studies make use of mouse embryonic fibroblasts (MEFs) from mouse models of genetically induced CIN to estimate the in vivo rate of CIN.…”

Section: How and Why Is Cin Measured In Vitro?mentioning

confidence: 99%

“…It is difficult to make broad statements about CIN tolerance, as there are many different forms and rates of CIN. However, aneuploid cells with elevated levels of CIN [17] had a growth benefit relative to euploid control cells in non-standard, stressful culture conditions (i.e., serum-free conditions, and exposure to chemotherapeutic drug 5-Fluorouracil), but a growth defect under normal conditions. [69] This suggests that CIN may have selective advantages specifically in stressful, or non-standard growth conditions.…”

Section: Cin Can Have Highly Differential Effects On Cellsmentioning

confidence: 99%

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CIN and Aneuploidy: Different Concepts, Different Consequences

Schukken

Foijer

2017

BioEssays

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Chromosomal instability (CIN) and aneuploidy are similar concepts but not synonymous. CIN is the process that leads to chromosome copy number alterations, and aneuploidy is the result. While CIN and resulting aneuploidy often cause growth defects, they are also selected for in cancer cells. Although such contradicting fates may seem paradoxical at first, they can be better understood when CIN and aneuploidy are assessed separately, taking into account the in vitro or in vivo context, the rate of CIN, and severity of the aneuploid karyotype. As CIN can only be measured in living cells, which proves to be technically challenging in vivo, aneuploidy is more frequently quantified. However, CIN rates might be more predictive for tumor outcome than assessing aneuploidy rates alone. In reviewing the literature, we therefore conclude that there is an urgent need for new models in which we can monitor chromosome mis-segregation and its consequences in vivo. Also see the video abstract here: https://youtu.be/fL3LxZduchg

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“…The same applies to those sSMCs in which three different haplotypes at the level of the marker chromosome and biparental origin of the single nucleotide polymorphisms (SNPs) along the normal homologs are detected, with the only difference that the trisomic rescue occurred on one of the two chromosomes of maternal origin. It is well known that anaphase lagging accounts for trisomy rescue of the supernumerary chromosome (Ly & Cleveland, ; Nicholson et al., ) which is then trapped within a micronucleus where massive shattering occurs after disruption of the nuclear envelope exposing DNA to the cytoplasm (Liu et al., ; Zhang et al., ). As a consequence, the supernumerary chromosome is eliminated in one daughter cell, thus explaining the presence of the normal cell line.…”

Section: Reconstruction and Formation Mechanisms Of Ssmcmentioning

confidence: 99%

Small supernumerary marker chromosomes: A legacy of trisomy rescue?

et al. 2018

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We studied by a whole genomic approach and trios genotyping, 12 de novo, nonrecurrent small supernumerary marker chromosomes (sSMC), detected as mosaics during pre‐ or postnatal diagnosis and associated with increased maternal age. Four sSMCs contained pericentromeric portions only, whereas eight had additional non‐contiguous portions of the same chromosome, assembled together in a disordered fashion by repair‐based mechanisms in a chromothriptic event. Maternal hetero/isodisomy was detected with a paternal origin of the sSMC in some cases, whereas in others two maternal alleles in the sSMC region and biparental haplotypes of the homologs were detected. In other cases, the homologs were biparental while the sSMC had the same haplotype of the maternally inherited chromosome. These findings strongly suggest that most sSMCs are the result of a multiple‐step mechanism, initiated by maternal meiotic nondisjunction followed by postzygotic anaphase lagging of the supernumerary chromosome and its subsequent chromothripsis.

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“…Mitotic exit is precisely and tightly coordinated to ensure that cell division occurs only after chromosomes are properly replicated and equally segregated between the two new daughter cells. Problems during mitotic exit can lead to genomic instability, genetic diseases and neurodegenerative disorders [133,134]. Various surveillance mechanisms or checkpoints delay mitotic progression to guarantee faithful inheritance of the genetic material.…”

Section: Mitosismentioning

confidence: 99%

The regulation of Net1/Cdc14 by the Hog1 MAPK upon osmostress unravels a new mechanism regulating mitosis

et al. 2020

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During evolution, cells have developed a plethora of mechanisms to optimize survival in a changing and unpredictable environment. In this regard, they have evolved networks that include environmental sensors, signaling transduction molecules and response mechanisms. Hog1 (yeast) and p38 (mammals) stress-activated protein kinases (SAPKs) are activated upon stress and they drive a full collection of cell adaptive responses aimed to maximize survival. SAPKs are extensively used to learn about the mechanisms through which cells adapt to changing environments. In addition to regulating gene expression and metabolism, SAPKs control cell cycle progression. In this review, we will discuss the latest findings related to the SAPK-driven regulation of mitosis upon osmostress in yeast.

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“…To achieve this, membrane fragments first coat the individual chromosomes, which only then agglomerate and coalesce into distinct nuclei again (Schooley et al, 2012). Such single chromosome micronuclei form the basis for the microcell-mediated transfer of exogenous chromosome material into host cells (Meaburn et al, 2005;Fenech et al, 2011), which even enabled the successful integration of entire intact human chromosomes 8, 13, 18 and 21 into human isogenic embryonic stem cells (Kazuki et al, 2014;Hiramatsu et al, 2019) as well as chromosomes 3, 7 and 13 into the karyotypic stable, mismatch repair deficient colorectal cancer cell line DLD-1 (Upender et al, 2004;Nicholson et al, 2015;Rutledge and Cimini, 2016;Wangsa et al, 2019). A missegregated micronucleus can also undergo massive shattering and restructuring before these pieces rejoin again and form a new single chromatid, which can then become part of the nucleus again.…”

Section: and Beyond: Re-fusion Entosis Neosis Meiomitosis And Polyploidizationmentioning

confidence: 99%

Somatic Sex: On the Origin of Neoplasms With Chromosome Counts in Uneven Ploidy Ranges

Haas

2021

Front. Cell Dev. Biol.

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Stable aneuploid genomes with nonrandom numerical changes in uneven ploidy ranges define distinct subsets of hematologic malignancies and solid tumors. The idea put forward herein suggests that they emerge from interactions between diploid mitotic and G0/G1 cells, which can in a single step produce all combinations of mono-, di-, tri-, tetra- and pentasomic paternal/maternal homologue configurations that define such genomes. A nanotube-mediated influx of interphase cell cytoplasm into mitotic cells would thus be responsible for the critical nondisjunction and segregation errors by physically impeding the proper formation of the cell division machinery, whereas only a complete cell fusion can simultaneously generate pentasomies, uniparental trisomies as well as biclonal hypo- and hyperdiploid cell populations. The term “somatic sex” was devised to accentuate the similarities between germ cell and somatic cell fusions. A somatic cell fusion, in particular, recapitulates many processes that are also instrumental in the formation of an abnormal zygote that involves a diploid oocyte and a haploid sperm, which then may further develop into a digynic triploid embryo. Despite their somehow deceptive differences and consequences, the resemblance of these two routes may go far beyond of what has hitherto been appreciated. Based on the arguments put forward herein, I propose that embryonic malignancies of mesenchymal origin with these particular types of aneuploidies can thus be viewed as the kind of flawed somatic equivalent of a digynic triploid embryo.

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“…In line with this hypothesis, yeast strains aneuploid in different chromosomes show various degrees of karyotypic and genomic instability, likely due to products from genes encoded on the aneuploid chromosomes [53,54]. Studies in human cells also suggest that aneuploidy itself may increase chromosome instability by affecting chromosome segregation in mitosis or by inducing defects in replication [55,56]. …”

Section: Aneuploidy In Mitosismentioning

(Expert classified)

The Consequences of Chromosome Segregation Errors in Mitosis and Meiosis

Potapova

Gorbsky

2017

Biology

151

116

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Mistakes during cell division frequently generate changes in chromosome content, producing aneuploid or polyploid progeny cells. Polyploid cells may then undergo abnormal division to generate aneuploid cells. Chromosome segregation errors may also involve fragments of whole chromosomes. A major consequence of segregation defects is change in the relative dosage of products from genes located on the missegregated chromosomes. Abnormal expression of transcriptional regulators can also impact genes on the properly segregated chromosomes. The consequences of these perturbations in gene expression depend on the specific chromosomes affected and on the interplay of the aneuploid phenotype with the environment. Most often, these novel chromosome distributions are detrimental to the health and survival of the organism. However, in a changed environment, alterations in gene copy number may generate a more highly adapted phenotype. Chromosome segregation errors also have important implications in human health. They may promote drug resistance in pathogenic microorganisms. In cancer cells, they are a source for genetic and phenotypic variability that may select for populations with increased malignance and resistance to therapy. Lastly, chromosome segregation errors during gamete formation in meiosis are a primary cause of human birth defects and infertility. This review describes the consequences of mitotic and meiotic errors focusing on novel concepts and human health.

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“…77 Moreover, cultured hPSCs tend to acquire trisomy of chromosome 12, which is the most common chromosomal aberration in germ cell tumors, 43 and trisomy of chromosome 13, which confers a distinctive cytokinesis failure phenotype to colon cancer cells. 66 Although the spectrum and degree of aneuploidy differ among tumors, many human cancers share recurrent aneuploidies. 78 It is currently believed that tumor-specific aneuploidies coexist with recurrent aneuploidies across tumors.…”

Section: Aneuploidy and Cancer: Cell Type Genomic Background And Envmentioning

confidence: 99%

“…In particular, chromosome segregation errors (specifically chromatin bridges, which typically arise as a result of DNA damage) can lead to the accumulation of postmitotic DNA damage due to the “trapping” of chromatin bridges in the cleavage furrow . Moreover, trisomic colon cancer cells display a higher rate of chromosome missegregation than that of euploid ones, and the capacity of accurate chromosome segregation decreases in a discontinuous way compared to chromosome number changes . Indeed, yeast cells with a ploidy between 1.5 and 2 are more susceptible to chromosome missegregation than those with a near haploid karyotype .…”

Section: Tumor‐protecting and Tumor‐promoting Effects Of Aneuploidymentioning

confidence: 99%

“…Reduced BUB1 expression favors the development of thymic lymphoma and colon cancer in tp53 +/─ and apc Min/+ mice, respectively, but suppresses prostatic intraepithelial neoplasia in pten +/─ mice and does not alter the frequency of pituitary tumors and sarcoma formation in the rb +/─ model . Moreover, cultured hPSCs tend to acquire trisomy of chromosome 12, which is the most common chromosomal aberration in germ cell tumors, and trisomy of chromosome 13, which confers a distinctive cytokinesis failure phenotype to colon cancer cells …”

Section: Aneuploidy and Cancer: Cell Type Genomic Background And Envi...mentioning

confidence: 99%

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Aneuploidy: Cancer strength or vulnerability?

Simonetti

Bruno

Padella

et al. 2018

Intl Journal of Cancer

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Aneuploidy is a very rare and tissue-specific event in normal conditions, occurring in a low number of brain and liver cells. Its frequency increases in age-related disorders and is one of the hallmarks of cancer. Aneuploidy has been associated with defects in the spindle assembly checkpoint (SAC). However, the relationship between chromosome number alterations, SAC genes and tumor susceptibility remains unclear. Here, we provide a comprehensive review of SAC gene alterations at genomic and transcriptional level across human cancers and discuss the oncogenic and tumor suppressor functions of aneuploidy. SAC genes are rarely mutated but frequently overexpressed, with a negative prognostic impact on different tumor types. Both increased and decreased SAC gene expression show oncogenic potential in mice. SAC gene upregulation may drive aneuploidization and tumorigenesis through mitotic delay, coupled with additional oncogenic functions outside mitosis. The genomic background and environmental conditions influence the fate of aneuploid cells. Aneuploidy reduces cellular fitness. It induces growth and contact inhibition, mitotic and proteotoxic stress, cell senescence and production of reactive oxygen species. However, aneuploidy confers an evolutionary flexibility by favoring genome and chromosome instability (CIN), cellular adaptation, stem cell-like properties and immune escape. These properties represent the driving force of aneuploid cancers, especially under conditions of stress and pharmacological pressure, and are currently under investigation as potential therapeutic targets. Indeed, promising results have been obtained from synthetic lethal combinations exploiting CIN, mitotic defects, and aneuploidy-tolerating mechanisms as cancer vulnerability.

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Chromosome mis-segregation and cytokinesis failure in trisomic human cells

Cited by 95 publications

References 74 publications

Tools used to assay genomic instability in cancers and cancer meiomitosis

Natural antisense transcript of Period2, Per2AS, regulates the amplitude of the mouse circadian clock

Cellular Stress Associated with Aneuploidy

Natural Antisense Transcript ofPeriod2, Per2AS, regulates the amplitude of the mouse circadian clock

CIN and Aneuploidy: Different Concepts, Different Consequences

Small supernumerary marker chromosomes: A legacy of trisomy rescue?

The regulation of Net1/Cdc14 by the Hog1 MAPK upon osmostress unravels a new mechanism regulating mitosis

Somatic Sex: On the Origin of Neoplasms With Chromosome Counts in Uneven Ploidy Ranges

The Consequences of Chromosome Segregation Errors in Mitosis and Meiosis

Aneuploidy: Cancer strength or vulnerability?

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