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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“…Further investigation is needed to determine whether decreased purifying selection can also cause the accumulation of cells that are genetically unstable and karyotypically abnormal (Sheltzer et al 2011;Zhu et al 2012;Nicholson et al 2015), since such a population from which rare cells with high proliferative and hence tumorigenic potential may arise could cause cancer as individuals age.…”

Section: Bub1bmentioning

confidence: 99%

Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo

et al. 2016

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Aneuploidy, an imbalanced karyotype, is a widely observed feature of cancer cells that has long been hypothesized to promote tumorigenesis. Here we evaluate the fitness of cells with constitutional trisomy or chromosomal instability (CIN) in vivo using hematopoietic reconstitution experiments. We did not observe cancer but instead found that aneuploid hematopoietic stem cells (HSCs) exhibit decreased fitness. This reduced fitness is due at least in part to the decreased proliferative potential of aneuploid hematopoietic cells. Analyses of mice with CIN caused by a hypomorphic mutation in the gene Bub1b further support the finding that aneuploidy impairs cell proliferation in vivo. Whereas nonregenerating adult tissues are highly aneuploid in these mice, HSCs and other regenerative adult tissues are largely euploid. These findings indicate that, in vivo, mechanisms exist to select against aneuploid cells.

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“…Analysis of trisomy of chromosome 7 or 13 in the p53-deficient cancer cell line DLD1 revealed increased chromosome missegregation of the extra chromosome and a frequent cytokinesis failure in trisomy 13 (ref. 27 ). Yet, no systematic analysis of the effects of aneuploidy on the maintenance of genome stability has been performed in higher eukaryotes so far.…”

mentioning

confidence: 99%

The presence of extra chromosomes leads to genomic instability

Ozeri-Galai²,

et al. 2016

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Aneuploidy is a hallmark of cancer and underlies genetic disorders characterized by severe developmental defects, yet the molecular mechanisms explaining its effects on cellular physiology remain elusive. Here we show, using a series of human cells with defined aneuploid karyotypes, that gain of a single chromosome increases genomic instability. Next-generation sequencing and SNP-array analysis reveal accumulation of chromosomal rearrangements in aneuploids, with break point junction patterns suggestive of replication defects. Trisomic and tetrasomic cells also show increased DNA damage and sensitivity to replication stress. Strikingly, we find that aneuploidy-induced genomic instability can be explained by the reduced expression of the replicative helicase MCM2-7. Accordingly, restoring near-wild-type levels of chromatin-bound MCM helicase partly rescues the genomic instability phenotypes. Thus, gain of chromosomes triggers replication stress, thereby promoting genomic instability and possibly contributing to tumorigenesis.

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“…As a result, cells with extra chromosomes exhibit impaired protein folding, cytoplasmic foci of aggregated proteins, increased proteasomal activity, and sensitivity to conditions that disrupt proteostasis 14,16,17 . In addition, aneuploid cells suffer from genomic instability characterized by replication stress, accumulation of DNA damage, and increased chromosomal aberrations 3,[18][19][20] .…”

mentioning

confidence: 99%

Genotoxic stress in constitutive trisomies induces autophagy and the innate immune response via the cGAS-STING pathway

et al. 2021

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Gain of even a single chromosome leads to changes in human cell physiology and uniform perturbations of specific cellular processes, including downregulation of DNA replication pathway, upregulation of autophagy and lysosomal degradation, and constitutive activation of the type I interferon response. Little is known about the molecular mechanisms underlying these changes. We show that the constitutive nuclear localization of TFEB, a transcription factor that activates the expression of autophagy and lysosomal genes, is characteristic of human trisomic cells. Constitutive nuclear localization of TFEB in trisomic cells is independent of mTORC1 signaling, but depends on the cGAS-STING activation. Trisomic cells accumulate cytoplasmic dsDNA, which activates the cGAS-STING signaling cascade, thereby triggering nuclear accumulation of the transcription factor IRF3 and, consequently, upregulation of interferon-stimulated genes. cGAS depletion interferes with TFEB-dependent upregulation of autophagy in model trisomic cells. Importantly, activation of both the innate immune response and autophagy occurs also in primary trisomic embryonic fibroblasts, independent of the identity of the additional chromosome. Our research identifies the cGAS-STING pathway as an upstream regulator responsible for activation of autophagy and inflammatory response in human cells with extra chromosomes, such as in Down syndrome or other aneuploidy-associated pathologies.

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Aneuploidy and chromosomal instability in cancer: a jackpot to chaos

2015

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Genomic instability (GIN) is a hallmark of cancer cells that facilitates the acquisition of mutations conferring aggressive or drug-resistant phenotypes during cancer evolution. Chromosomal instability (CIN) is a form of GIN that involves frequent cytogenetic changes leading to changes in chromosome copy number (aneuploidy). While both CIN and aneuploidy are common characteristics of cancer cells, their roles in tumor initiation and progression are unclear. On the one hand, CIN and aneuploidy are known to provide genetic variation to allow cells to adapt in changing environments such as nutrient fluctuations and hypoxia. Patients with constitutive aneuploidies are more susceptible to certain types of cancers, suggesting that changes in chromosome copy number could positively contribute to cancer evolution. On the other hand, chromosomal imbalances have been observed to have detrimental effects on cellular fitness and might trigger cell cycle arrest or apoptosis. Furthermore, mouse models for CIN have led to conflicting results. Taken together these findings suggest that the relationship between CIN, aneuploidy and cancer is more complex than what was previously anticipated. Here we review what is known about this complex ménage à trois, discuss recent evidence suggesting that aneuploidy, CIN and GIN together promote a vicious cycle of genome chaos. Lastly, we propose a working hypothesis to reconcile the conflicting observations regarding the role of aneuploidy and CIN in tumorigenesis.

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The diverse consequences of aneuploidy

2019

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3D genome of multiple myeloma reveals spatial genome disorganization associated with copy number variations

et al. 2017

Nat Commun

104

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The Hi-C method is widely used to study the functional roles of the three-dimensional (3D) architecture of genomes. Here, we integrate Hi-C, whole-genome sequencing (WGS) and RNA-seq to study the 3D genome architecture of multiple myeloma (MM) and how it associates with genomic variation and gene expression. Our results show that Hi-C interaction matrices are biased by copy number variations (CNVs) and can be used to detect CNVs. Also, combining Hi-C and WGS data can improve the detection of translocations. We find that CNV breakpoints significantly overlap with topologically associating domain (TAD) boundaries. Compared to normal B cells, the numbers of TADs increases by 25% in MM, the average size of TADs is smaller, and about 20% of genomic regions switch their chromatin A/B compartment types. In summary, we report a 3D genome interaction map of aneuploid MM cells and reveal the relationship among CNVs, translocations, 3D genome reorganization, and gene expression regulation.

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Aneuploidy as a promoter and suppressor of malignant growth

et al. 2021

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Chromosomal instability: A common feature and a therapeutic target of cancer

Tanaka

Hirota

2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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The molecular origins and pathophysiological consequences of micronuclei: New insights into an age-old problem

Guo

Liang

et al. 2019

Mutation Research/Reviews in Mutation Research

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Centrosome amplification, chromosomal instability and cancer: mechanistic, clinical and therapeutic issues

Cosenza

Krämer

2015

Chromosome Res

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Centrosomes, the main microtubule-organizing centers in most animal cells, are of crucial importance for the assembly of a bipolar mitotic spindle and subsequent faithful segregation of chromosomes into two daughter cells. Centrosome abnormalities can be found in virtually all cancer types and have been linked to chromosomal instability (CIN) and tumorigenesis. Although our knowledge on centrosome structure, replication, and amplification has greatly increased within recent years, still only very little is known on nature, causes, and consequences of centrosome aberrations in primary tumor tissues. In this review, we summarize our current insights into the mechanistic link between centrosome aberrations, aneuploidy, CIN and tumorigenesis. Mechanisms of induction and cellular consequences of aneuploidy, tetraploidization and CIN, as well as origin and effects of supernumerary centrosomes will be discussed. In addition, animal models for both CIN and centrosome amplification will be outlined. Finally, we describe approaches to exploit centrosome amplification, aneuploidy and CIN for novel and specific anticancer treatment strategies based on the modulation of chromosome missegregation rates.

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Chromosome mis-segregation and cytokinesis failure in trisomic human cells

Cited by 95 publications

References 74 publications

Aneuploidy impairs hematopoietic stem cell fitness and is selected against in regenerating tissues in vivo

The presence of extra chromosomes leads to genomic instability

Genotoxic stress in constitutive trisomies induces autophagy and the innate immune response via the cGAS-STING pathway

Aneuploidy and chromosomal instability in cancer: a jackpot to chaos

The diverse consequences of aneuploidy

3D genome of multiple myeloma reveals spatial genome disorganization associated with copy number variations

Aneuploidy as a promoter and suppressor of malignant growth

Chromosomal instability: A common feature and a therapeutic target of cancer

The molecular origins and pathophysiological consequences of micronuclei: New insights into an age-old problem

Centrosome amplification, chromosomal instability and cancer: mechanistic, clinical and therapeutic issues

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