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 97 publications

(99 citation statements)

References 74 publications

(125 reference statements)

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“…al ( 7 ) cites Nicholson et. al ( 8 ) , traditional citation indices report this citation by displaying the title of the citing paper and other bibliographic information such as the journal, year published, and other metadata ( Figure 1). Traditional citation indices do not have the capacity to examine contextual information or how the citing paper used the citation, such as whether it was made to support or dispute the findings of the cited paper or if it was made in the introduction or the discussion section.…”

Section: Introductionmentioning

confidence: 99%

scite: a smart citation index that displays the context of citations and classifies their intent using deep learning

Nicholson¹,

Mordaunt²,

Lopez³

et al. 2021

Preprint

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Citation indices are tools used by the academic community for research and research evaluation which aggregate scientific literature output and measure scientific impact by collating citation counts. Citation indices help measure the interconnections between scientific papers but fall short because they only display paper titles, authors, and the date of publications, and fail to communicate contextual information about why a citation was made. The usage of citations in research evaluation without due consideration to context can be problematic, if only because a citation that disputes a paper is treated the same as a citation that supports it. To solve this problem, we have used machine learning and other techniques to develop a "smart citation index" called scite, which categorizes citations based on context. Scite shows how a citation was used by displaying the surrounding textual context from the citing paper, and a classification from our deep learning model that indicates whether the statement provides supporting or disputing evidence for a referenced work, or simply mentions it. Scite has been developed by analyzing over 23 million full-text scientific articles and currently has a database of more than 800 million classified citation statements. Here we describe how scite works and how it can be used to further research and research evaluation.

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“…Similar observations were made in higher eukaryotes 22 . For example, a comparison between trisomic and diploid human cells has revealed that aneuploid cells are characterized by increased frequency of lagging chromosomes in anaphase 23,24 . Thus, this evidence points at aneuploidy as an instigator of genome instability 20 .…”

Section: Introductionmentioning

confidence: 99%

Short-term molecular consequences of chromosome mis-segregation for genome stability

Feudis

Garribba

Martis

et al. 2022

Preprint

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Genome instability is a hallmark of cancer. The most common form of genome instability is chromosomal instability (CIN), a condition in which cells mis-segregate their chromosomes during cell division. CIN leads to aneuploidy, a state of karyotype imbalance, often found in tumors. Although the causal relationship between CIN and aneuploidy is well established, evidence is limited for a direct involvement of aneuploidy in promoting CIN. Here, we show that aneuploid cells experience DNA replication stress in their first S-phase and precipitate in a state of continuous CIN, eventually accumulating complex karyotypes. Mechanistically, we find that aneuploid cells fire dormant replication origins through a Dbf4-dependent kinase (DDK)-driven mechanism and complete replication of genomic loci through mitotic DNA synthesis (MiDAS). By following the fate of aneuploid cells, we also show that, when they divide, DNA damage can be distributed asymmetrically between daughter cells, and this may partially explain why some aneuploid cells are able to continue proliferating and others stop dividing. We further found that cycling aneuploid cells display lower karyotype complexity compared to arrested ones and increased expression of gene signatures associated to DNA repair. Interestingly, by stratifying aneuploid human cancer cells by their doubling times, we found the same DNA repair signatures to be upregulated in highly-proliferative cancer cells, which might enable them to keep proliferating despite the disadvantage conferred by aneuploidy-induced genome instability. In summary, our study reveals the origins of genome instability following induction of aneuploidy and indicates the aneuploid state of cancer cells as a point mutation-independent source of genome instability, providing an explanation for the high occurrence of aneuploidy in tumors.

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“…In this study, using CRISPR/Cas9 system, we successfully established a stable line that carries mAID tagged EWSR1 alleles ( AID-EWSR1/AID-EWSR1 ) at a homozygous level in OsTIR1 expressing DLD-1 cells (Hassebroek et al, 2020). The DLD-1 (a colorectal cancer) cell line was utilized in this study because it carries a near-diploid karyotype, and has been utilized as a model cell line to study the induction of aneuploidy (Nicholson et al, 2015, Lengauer et al, 1997b). Here, we show that the knockdown of EWSR1 for one cell cycle is sufficient to induce lagging chromosomes and aneuploidy without inducing mitotic arrest.…”

Section: Introductionmentioning

confidence: 99%

EWSR1 prevents the induction of aneuploidy by regulating the localization of Aurora B at inner centromere

Kim

Park

Schulz

et al. 2022

Preprint

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EWSR1 (Ewing sarcoma breakpoint region 1) was originally identified as a part of an aberrant EWSR1/FLI1 fusion gene in Ewing sarcoma, the second most common pediatric bone cancer. Due to formation of the EWSR1/FLI1 fusion gene in the tumor genome, the cell loses one wild type EWSR1 allele. Our previous study demonstrated that the loss of ewsr1a (homologue of human EWSR1) in zebrafish leads to the high incidence of mitotic dysfunction, of aneuploidy, and of tumorigenesis in the tp53 mutant background. To dissect the molecular function of EWSR1, we successfully established a stable DLD-1 cell line that enables a conditional knockdown of EWSR1 using Auxin Inducible Degron (AID) system. When both EWSR1 genes of DLD-1 cell were tagged with mini-AID using CRISPR/Cas9 system, treatment of the (AID-EWSR1/AID-EWSR1) DLD-1 cells with a plant-based Auxin (AUX) led to the significant levels of degradation of AID-EWSR1 proteins. During anaphase, the EWSR1 knockdown (AUX+) cells displayed higher incidence of lagging chromosomes compared to the control (AUX-) cells. This defect was proceeded by a lower incidence of the localization of Aurora B at inner centromeres, and by a higher incidence of the protein at kinetochores compared to the control cells during pro/metaphase. Despite these defects, the EWSR1 knockdown cells did not arrest at mitosis, suggesting that the cell lacks the error correction mechanism. Significantly, the EWSR1 knockdown (AUX+) cells induced higher incidence of aneuploidy compared to the control (AUX-) cells. Since our previous study demonstrated that EWSR1 interacts with the key mitotic kinase, Aurora B, we generated replacement lines of EWSR1-mCherry and EWSR1:R565A-mCherry (a mutant that has low affinity for Aurora B) in the (AID-EWSR1/AID-EWSR1) DLD-1 cells. The EWSR1-mCherry rescued the high incidence of aneuploidy of EWSR1 knockdown cells, whereas EWSR1-mCherry:R565A failed to rescue the phenotype. Together, we demonstrate that EWSR1 is essential to prevent aneuploidy through interaction with Aurora B, most likely by regulating the localization of Aurora B at centromere.

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“…In this study, using CRISPR/Cas9 system, we successfully established a stable line that is homozygous for mAID tagged EWSR1 alleles ( AID-EWSR1/AID-EWSR1 ) at a homozygous level in OsTIR1 expressing DLD-1 cells ( Hassebroek et al, 2020 ). The DLD-1 (a colorectal cancer) cell line was utilized in this study because it carries a near-diploid karyotype, and has been utilized as a model cell line to study the induction of aneuploidy ( Lengauer et al, 1997 ; Nicholson et al, 2015 ). Here, we show that the knockdown of EWSR1 for 1 cell cycle is sufficient to induce lagging chromosomes and aneuploidy without inducing mitotic arrest.…”

Section: Introductionmentioning

confidence: 99%

EWSR1 prevents the induction of aneuploidy through direct regulation of Aurora B

Kim

Park²,

Schulz³

et al. 2023

Front. Cell Dev. Biol.

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EWSR1 (Ewing sarcoma breakpoint region 1) was originally identified as a part of an aberrant EWSR1/FLI1 fusion gene in Ewing sarcoma, the second most common pediatric bone cancer. Due to formation of the EWSR1/FLI1 fusion gene in the tumor genome, the cell loses one wild type EWSR1 allele. Our previous study demonstrated that the loss of ewsr1a (homologue of human EWSR1) in zebrafish leads to the high incidence of mitotic dysfunction, of aneuploidy, and of tumorigenesis in the tp53 mutant background. To dissect the molecular function of EWSR1, we successfully established a stable DLD-1 cell line that enables a conditional knockdown of EWSR1 using an Auxin Inducible Degron (AID) system. When both EWSR1 genes of DLD-1 cell were tagged with mini-AID at its 5′-end using a CRISPR/Cas9 system, treatment of the (AID-EWSR1/AID-EWSR1) DLD-1 cells with a plant-based Auxin (AUX) led to the significant levels of degradation of AID-EWSR1 proteins. During anaphase, the EWSR1 knockdown (AUX+) cells displayed higher incidence of lagging chromosomes compared to the control (AUX-) cells. This defect was proceeded by a lower incidence of the localization of Aurora B at inner centromeres, and by a higher incidence of the protein at Kinetochore proximal centromere compared to the control cells during pro/metaphase. Despite these defects, the EWSR1 knockdown cells did not undergo mitotic arrest, suggesting that the cell lacks the error correction mechanism. Significantly, the EWSR1 knockdown (AUX+) cells induced higher incidence of aneuploidy compared to the control (AUX-) cells. Since our previous study demonstrated that EWSR1 interacts with the key mitotic kinase, Aurora B, we generated replacement lines of EWSR1-mCherry and EWSR1:R565A-mCherry (a mutant that has low affinity for Aurora B) in the (AID-EWSR1/AID-EWSR1) DLD-1 cells. The EWSR1-mCherry rescued the high incidence of aneuploidy of EWSR1 knockdown cells, whereas EWSR1-mCherry:R565A failed to rescue the phenotype. Together, we demonstrate that EWSR1 prevents the induction of lagging chromosomes, and of aneuploidy through the interaction with Aurora B.

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“…Aneuploidy, mostly of which is monosomy or trisomy, de ned as a chromosome number that is not an exact multiple of the usually haploid number, affects 50%-80% of preimplantation embryos, 10-40% of pregnancies, and 0.3% of newborns [1,2]. It is the leading cause of miscarriages and developmental defects in humans [3,4]. Monosomic or trisomic babies that do survive are associated with well-de ned syndromes, including Turner, Down, Edwards, Patau, Klinefelter, and Superfemale syndrome.…”

Section: Introductionmentioning

confidence: 99%

Are there common mechanisms of aneuploidy-related abortion and defects in fetus?

Xie

Lü

Huang

et al. 2020

Preprint

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Background: Monosomies and trisomies, as the most common aneuploid abnormalities, are the leading causes of miscarriages and fetal defects in humans. Although there is evidence suggested that aneuploid may have some common aspects, their common mechanism still remains unclear. This studies objective was to explore the common mechanism of monosomies and trisomies, with a purpose to identify some critical biomarkers and pathway so as to early diagnosis and effective therapy.Methods: We obtained the mRNA expression profile of GSE114559 including 101 samples data from GEO database. These data include normal, every monosomic, and trisomic transcriptome. We conducted Limma analysis by using the adj. p<0.05 and |FC|>1 criteria to identify all monosomy-related, trisomy-related differentially expressed genes (DEGs), and also to found their overlapping DEGs through Venn diagram. We then performed Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses, protein-protein interaction(PPI) network analysis to find the functional, pathways and hub genes in these DEGs. We carried out weighted correlation network analysis (WGCNA) to further detect the candidate genes and pathways related to all DEGs and their overlappling DEGs. Finally, we further used qPCR to certify pathological change of specific genes. Results: We identified all monosomy-related, trisomy-related DEGs, and their overlapping DEGs which were enriched by spliceosome, thyroid hormone, infection-related genes and signalling pathways. We also found that epigenetic related pathways were significantly enriched in the DEGs of monosomies by GO, KEGG. We explode the hub gene and module in the DEGs of monosomies and the overlapping DEGs by PPI. Then, we found that spliceosome, thyroid hormone, infection-related genes and signalling pathways were enriched in all DEGs group and the overlapping DEGs group by weighted correlation network analysis (WGCNA). Finally, we certified some hub gene in the trisomy 21, 47, XYY samples from clinical patients by qPCR which were consistent with results of PPI analysis.Conclusion: Our study indicates the potential common mechanism underlining spliceosome, thyroid hormone and infection-related signalling pathways for both monosomies and trisomies, and the mechanism underling epigenetic for monosomies.

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“…2A ). If all such unusual segregation events are not properly coordinated, there is a high probability of lagging chromosomes and mis-segregation, resulting in daughter cells with chromosomal abnormalities (Cimini, Howell et al, 2001 ; Nicholson, Macedo et al, 2015 ). In addition, uniparental disomy, which is extremely rare in normal mitosis but can occur in differentiated cells, can predispose up to one-third of hepatocytes to loss of heterozygosity (Fig.…”

Section: Introductionmentioning

confidence: 99%

Origins of cancer: ain’t it just mature cells misbehaving?

Cho,

Brown,

Mills

2024

EMBO J

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A pervasive view is that undifferentiated stem cells are alone responsible for generating all other cells and are the origins of cancer. However, emerging evidence demonstrates fully differentiated cells are plastic, can be coaxed to proliferate, and also play essential roles in tissue maintenance, regeneration, and tumorigenesis. Here, we review the mechanisms governing how differentiated cells become cancer cells. First, we examine the unique characteristics of differentiated cell division, focusing on why differentiated cells are more susceptible than stem cells to accumulating mutations. Next, we investigate why the evolution of multicellularity in animals likely required plastic differentiated cells that maintain the capacity to return to the cell cycle and required the tumor suppressor p53. Finally, we examine an example of an evolutionarily conserved program for the plasticity of differentiated cells, paligenosis, which helps explain the origins of cancers that arise in adults. Altogether, we highlight new perspectives for understanding the development of cancer and new strategies for preventing carcinogenic cellular transformations from occurring.

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“…Various approaches have been developed to model specific whole‐chromosome and arm‐level aneuploidies, including microcell‐mediated chromosome transfer (Upender et al , 2004 ), Cre‐lox recombination of homologs to generate acentric and dicentric chromosomes (Thomas et al , 2018 ), CRISPR/Cas9‐mediated arm‐level and whole‐chromosome deletion (Adikusuma et al , 2017 ; Taylor et al , 2018 ), and centromere inactivation of chromosome Y by inducible degradation of CENP‐A (Ly et al , 2016 ). Although these methods have generated valuable cell lines with particular chromosomal gains and losses (Nicholson et al , 2015 ; Passerini et al , 2016 ), all of these approaches rely on clonal expansion, and therefore cells may have evolved during cell culture following the initial karyotype change. Complementary to these targeted studies, others have assessed the short‐ and longer‐term consequences of random karyotype changes in human cells predominantly after mitotic checkpoint inhibition (Santaguida et al , 2017 ; Soto et al , 2017 ; Viganó et al , 2018 ; Hintzen et al , 2022 ).…”

Section: Introductionmentioning

confidence: 99%

A kinesin‐based approach for inducing chromosome‐specific mis‐segregation in human cells

et al. 2023

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Various cancer types exhibit characteristic and recurrent aneuploidy patterns. The origins of these cancer type‐specific karyotypes are still unknown, partly because introducing or eliminating specific chromosomes in human cells still poses a challenge. Here, we describe a novel strategy to induce mis‐segregation of specific chromosomes in different human cell types. We employed Tet repressor or nuclease‐dead Cas9 to link a microtubule minus‐end‐directed kinesin (Kinesin14VIb) from Physcomitrella patens to integrated Tet operon repeats and chromosome‐specific endogenous repeats, respectively. By live‐ and fixed‐cell imaging, we observed poleward movement of the targeted loci during (pro)metaphase. Kinesin14VIb‐mediated pulling forces on the targeted chromosome were counteracted by forces from kinetochore‐attached microtubules. This tug‐of‐war resulted in chromosome‐specific segregation errors during anaphase and revealed that spindle forces can heavily stretch chromosomal arms. By single‐cell whole‐genome sequencing, we established that kinesin‐induced targeted mis‐segregations predominantly result in chromosomal arm aneuploidies after a single cell division. Our kinesin‐based strategy opens the possibility to investigate the immediate cellular responses to specific aneuploidies in different cell types; an important step toward understanding how tissue‐specific aneuploidy patterns evolve.

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“…While aneuploidy arises as a consequence of errors during mitosis, aneuploidy has also been shown to be a driver of ongoing mitotic errors, a phenomenon termed chromosomal instability (CIN) (25,26,28,(36)(37)(38)(39). The induction of CIN has also been linked to gene imbalances (25,39), and recent work shows that CIN levels specifically correlate to the amount of gained coding genes (40).…”

Section: Introductionmentioning

confidence: 99%

Reduction of chromosomal instability and inflammation is a common aspect of adaptation to aneuploidy

Hintzen,

Schubert,

Soto

et al. 2023

Preprint

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Aneuploidy, while detrimental to untransformed cells, is notably prevalent in cancer cells. This indicates that cancer cells have the ability to surmount the initial stress responses associated with aneuploidy, enabling rapid proliferation despite aberrant karyotypes. To generate more insight into key processes and requirements underlying the adaptation to aneuploidy, we generated a panel of aneuploid clones in p53-deficient RPE-1 cells and studied their behavior over time. As expected,de novogenerated aneuploid clones initially displayed reduced fitness, enhanced levels of chromosomal instability and an upregulated inflammatory response. Intriguingly, after a prolonged period of culturing, aneuploid clones exhibited increased proliferation rates while maintaining aberrant karyotypes, indicative of an adaptive response to the aneuploid state. Interestingly, all adapted clones displayed reduced chromosomal instability (CIN) and reduced inflammatory signaling, suggesting that these are common aspects of adaptation to aneuploidy. Collectively, our data suggests that CIN and concomitant inflammation are key processes that require correction to allow for fast growth. Finally, we provide evidence that amplification of oncogenic KRAS can promote adaptation.

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“…In addition, studies in yeast (Sheltzer et al 2011, Zhu et al 2012) and more recently in human cells (Nicholson et al 2015, Passerini et al 2016 have shown that the presence of a single extra chromosome appears to be sufficient to initiate further chromosome missegregation events, with mechanisms underlying this beginning to be elucidated. In some cases, aneuploidydriven CIN appears to depend upon deregulated gene expression of specific genes (Nicholson et al 2015), and as such may depend upon the identity of the chromosome in aneuploidy. In another case, a global increase in DNA replication stress was observed, that precipitated further genomic instability (Passerini et al 2016).…”

Section: Mechanisms Driving Chromosomal Instabilitymentioning

confidence: 99%

“…Gross changes in chromosome number including polyploidy have been shown to deregulate the genome in yeast (Storchova et al 2006) and mammalian (Li et al 1997) systems. In addition, studies in yeast (Sheltzer et al 2011, Zhu et al 2012) and more recently in human cells (Nicholson et al 2015, Passerini et al 2016 have shown that the presence of a single extra chromosome appears to be sufficient to initiate further chromosome missegregation events, with mechanisms underlying this beginning to be elucidated. In some cases, aneuploidydriven CIN appears to depend upon deregulated gene expression of specific genes (Nicholson et al 2015), and as such may depend upon the identity of the chromosome in aneuploidy.…”

Section: Mechanisms Driving Chromosomal Instabilitymentioning

confidence: 99%

Role of chromosomal instability in cancer progression

McClelland

2017

Endocrine Related Cancer

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Cancer cells often display chromosomal instability (CIN), a defect that involves loss or rearrangement of the cell's genetic material -chromosomes -during cell division. This process results in the generation of aneuploidy, a deviation from the haploid number of chromosomes, and structural alterations of chromosomes in over 90% of solid tumours and many haematological cancers. This trait is unique to cancer cells as normal cells in the body generally strictly maintain the correct number and structure of chromosomes. This key difference between cancer and normal cells has led to two important hypotheses: (i) cancer cells have had to overcome inherent barriers to changes in chromosomes that are not tolerated in non-cancer cells and (ii) CIN represents a cancer-specific target to allow the specific elimination of cancer cells from the body. To exploit these hypotheses and design novel approaches to treat cancer, a full understanding of the mechanisms driving CIN and how CIN contributes to cancer progression is required. Here, we will discuss the possible mechanisms driving chromosomal instability, how CIN may contribute to the progression at multiple stages of tumour evolution and possible future therapeutic directions based on targeting cancer chromosomal instability.

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“…These results might be explained by a strong effect of a specific karyotype, as overexpression of Spartin, a gene encoded on chromosome 13, was shown to lead to cytokinesis failure. 12 Haploid yeast strains that carry an additional copy of individual yeast chromosomes show increased rates of chromosome missegregation as well. 7 Thus, whether and how the gain of a single chromosome elevates w-CIN needs to be addressed in a more detailed study and on a broader range of cell lines and karyotypes.…”

Section: Aneuploidy Triggers Genomic Instability In Human Cellsmentioning

confidence: 99%

“…In support of such a link, aneuploidy often comes hand in hand with whole chromosome instability, elevated spontaneous mutagenesis and sensitivity to genotoxic stress, as it has been shown in yeast model aneuploid strains, and scattered evidence suggests this possibility also in mammalian cells. [6][7][8][9][10][11][12] However, molecular mechanisms that would explain how abnormal chromosome numbers lead to genome rearrangements remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Too much to handle — how gaining chromosomes destabilizes the genome

Passerini

Storchová

2016

Cell Cycle

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Most eukaryotic organisms are diploid, with 2 chromosome sets in their nuclei. Whole chromosomal aneuploidy, a deviation from multiples of the haploid chromosome number, arises from chromosome segregation errors and often has detrimental consequences for cells. In humans, numerical aneuploidy severely impairs embryonic development and the rare survivors develop disorders characterized by multiple pathologies. Moreover, as many as 75 % of malignant tumors display aneuploidy. Although the exact contribution of aneuploidy to tumorigenesis remains unclear, previous studies have suggested that aneuploidy may affect the maintenance of genome integrity. We found that human cells with extra chromosomes showed phenotypes suggestive of replication defects, a phenomenon which we went on to characterize as being due to the aneuploidy-driven downregulation of replication factors, in particular of the replicative helicase MCM2-7. Thus, missegregation of even a single chromosome can further promote genomic instability and thereby contribute to tumor development. In this review we will examine the possible causes of downregulation of replicative factors and discuss the consequences of genomic instability in aneuploid cells.

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Chromosome mis-segregation and cytokinesis failure in trisomic human cells

Cited by 97 publications

References 74 publications

scite: a smart citation index that displays the context of citations and classifies their intent using deep learning

Short-term molecular consequences of chromosome mis-segregation for genome stability

EWSR1 prevents the induction of aneuploidy by regulating the localization of Aurora B at inner centromere

EWSR1 prevents the induction of aneuploidy through direct regulation of Aurora B

Are there common mechanisms of aneuploidy-related abortion and defects in fetus?

Origins of cancer: ain’t it just mature cells misbehaving?

A kinesin‐based approach for inducing chromosome‐specific mis‐segregation in human cells

Reduction of chromosomal instability and inflammation is a common aspect of adaptation to aneuploidy

Role of chromosomal instability in cancer progression

Too much to handle — how gaining chromosomes destabilizes the genome

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