What would happen if a chromosome failed to attach to spindle fibers?

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• Published: 17 May 2010

Merotelic attachments and non-homologous end joining are the basis of chromosomal instability

Cell Division volume v, Article number:13 (2010) Cite this article

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Abstract

Although the big bulk of solid tumors show a combination of mitotic spindle defects and chromosomal instability, little is known about the mechanisms that govern the initial steps in tumorigenesis. The recent report of spindle-induced DNA damage provides evidence for a single mechanism responsible for the most prominent genetic defects in chromosomal instability. Spindle-induced Dna impairment is brought nigh by uncorrected merotelic attachments, which cause kinetochore baloney, chromosome breakage at the centromere, and possible activation of Deoxyribonucleic acid harm repair pathways. Although merotelic attachments are common early in mitosis, some escape detection past the kinetochore pathway. Equally a effect, a proportion of merotelic attachments gives rise to chromosome breakage in normal cells and in carcinomas. An intrinsic chromosome segregation defect might thus form the basis of tumor initiation. Nosotros propose a hypothesis in which merotelic attachments and chromosome breakage establish a feedback loop that results in relaxation of the spindle checkpoint and suppression of anti-proliferative pathways, thereby promoting carcinogenesis.

Introduction

Mitosis comprises a brief period of intense activity in the jail cell cycle. The segregation of sis chromatids into daughter cells involves moving the largest molecules encountered in nature (the chromosomes) over distances greater than the size of most organelles. To ensure sufficiently rapid chromosome segregation, almost eukaryotes connect each centromere to a parcel of parallel microtubules, termed the kinetochore fiber, forth which an outward-pulling force moves sister chromatids towards the spindle poles [1]. Chromosome segregation must be completed rapidly, since mitosis represses other prison cell functions [2–4], merely accurate distribution of sister chromatids over the two girl cells is essential for the genetic integrity of the organism. Cells thus impose control on the chromosome segregation machinery through a combination of mechanisms known as the spindle checkpoint. Before chromosomes are segregated, the cell must connect each kinetochore to a single spindle pole through a unmarried kinetochore fiber (amphitelic kinetochore attachment; Fig. 1a). This is the merely situation that guarantees the fidelity of chromosome segregation, and the cell will attempt to filibuster anaphase onset if these requirements are not fulfilled. Satisfaction of the mitotic checkpoint marks a bespeak of no render, and overall chromosome movement continues in anaphase even if spindle attachments are disturbed [5, 6]; this means that spindle errors can merely exist corrected inside a express fourth dimension window, and that undetected kinetochore attachment errors tin change the genetic makeup of daughter cells.

Figure 1

Spindle attachment defects. (a) In amphitelic zipper, the sister kinetochores are correctly connected to microtubules from reverse poles, resulting in a bioriented chromosome. (b) In a monotelic attachment, only 1 of the sis chromatids is continued to a spindle pole; the chromosome is mono-oriented. (c) In a syntelic attachment, both sister kinetochores are attached to a single spindle pole, and the chromosome is mono-oriented. (d) In a merotelic attachment, usually one or, rarely, both sister kinetochores are connected to both poles instead of i. Chromosomes are bioriented in merotelic attachments.

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In addition to correct amphitelic attachment, several errors can occur in microtubule/kinetochore coupling (Fig. 1b, c, d). Individual kinetochores might not attach (monotelic attachment), and are left backside once chromosome segregation is initiated at anaphase. Kinetochores of both sister chromatids might attach to microtubules from a single spindle pole (syntelic attachment), and run the risk of segregation into the incorrect girl cell. A single kinetochore might capture microtubules from both spindle poles (merotelic zipper), which places concrete stress on the centromere as the microtubules start to pull. The offset 2 errors outcome in loss of spindle tension, are sensed as a lack of kinetochore stretch, and trigger a strong bespeak for mitotic checkpoint activation [7]. Merotelic attachments generate kinetochore tension, however, and practise not always activate the spindle checkpoint [viii–x]. Although merotelic attachments are potentially harmful, they are relatively common in dividing cells, but are usually corrected early in mitosis [xi, 12]. The control of the mitotic spindle however is deregulated in most carcinomas, resulting in a self-amplifying loop of chromosomal instability. Recent advances underline the importance of spindle defects in the early on stages of tumorigenesis, and generate a particular interest in the role of spindle-induced chromosome breakage as the initiator of chromosomal instability [thirteen]. The aim of this paper is to discuss some of the signaling pathways that connect spindle defects, specifically merotelic attachments, to chromosome breakage and the regulation of prison cell cycle progression.

Coping with merotelic attachments

Uncorrected merotelic attachments pb to gains and losses of whole chromosomes, termed aneuploidy [eleven]. In add-on, uncorrected merotelic attachments tin can exert sufficient forcefulness to misconstrue individual kinetochores, which amercement centromeric chromatin and causes chromosome rupture [13]. The alterations that result from uncorrected merotelic attachments (aneuploidy as well equally losses and gains of chromosome arms) are amid the most frequently observed genomic defects in cancer [xiv, xv]. Since uncorrected merotelic attachments appear to exist common in solid tumors, thery are thought to be a driving strength backside the chromosomal instability (CIN) phenotype that accounts for approximately 85% of sporadic carcinomas [sixteen, 17]. The chromosome breakage that is associated with uncorrected merotelic attachments generates "reactive" chromosome arms that are able to fuse to intact chromosomes [17]. Such "reactive" artillery could initiate the self-propagating concatenation of instability termed the breakage-fusion-bridge wheel [eighteen]. Whereas the Dna breakage products of uncorrected merotelic attachments, whole chromosome arms, are specially mutual in low-grade tumors, complex translocation patterns are feature of high-grade carcinomas [19, 20]. In CIN tumors, uncorrected merotelic attachments might thus initiate genomic instability that is subsequently propagated past breakage-fusion-bridge cycles [17]. Although uncorrected merotelic attachments are common in CIN tumors that prove reduced spindle checkpoint control, some good for you cells likewise bear spindle defects. Genetic techniques using fluorescent probes that flank the centromere showed that a minor proportion of normal lymphocytes undergo physical separation of the long and short arms of a unmarried chromosome [21], indicating that some merotelic attachments lead inevitably to chromosome breakage. The uncorrected merotelic attachments responsible for the virtually important genomic alterations of CIN tumors thus occur occasionally in normal cells.

The prevalence of CIN in cancer and the evidence of uncorrected merotelic attachments in normal cells advise that correct chromosome segregation is a fundamental problem in development, however not fully resolved. Some species, for example Muntiacus muntjak, Potorous tridactylis, and Wallabia bicolor [22–24], get together their genome in a dozen or fewer chromosomes, with a concomitant reduction in centrosome number. Although low chromosome numbers reduce the number of kinetochores that require control in each cell partition, individual kinetochores still class merotelic attachments in Potorous tridactylis cells [25]. An extremely low chromosome number nonetheless appears to foreclose aneuploidy, thought to be i of the initiating events in tumorigenesis [16, 26]. Weather condition that readily induce aneuploidy in human and mouse cells but allow for loss or gain of the small sex chromosome Y2 in muntjac cells. Missegregation of the big chromosomes in muntjac is not tolerated due to cistron dosage effects [27]. Near mammals must live with the occasional aneuploid cell, yet, because they fully depend on spindle dynamics to detect and forestall chromosome missegregation [12, 25].

Since the classical mitotic checkpoint fails to detect a proportion of merotelic attachments [viii–x], a backup mechanism that detects the consequences of uncorrected merotelic attachments and prevents continuation of mitosis could provide a solution. In improver to aneuploidy, uncorrected merotelic attachments generate chromosome fragments, that is, the formation of double-strand breaks (DSB). DSB could thus indicate a chromosome segregation trouble to the cell. Intramitotic Deoxyribonucleic acid damage indeed produces an anaphase filibuster point; mammalian cells observe mitotic DNA breaks and respond by activating the spindle checkpoint [28–30]. The crosstalk between break repair and spindle control pathways might have a physiological function in the prevention of aneuploidy, since treatments that induce DNA harm cause aneuploidy in normal cells [31–33]. Although identification of damaged DNA seems a second-best solution, coupling DSB detection to anaphase filibuster serves the dual purpose of creating a fourth dimension window for repair and reattaching spindle fibers to the kinetochore (Fig. ii). The state of affairs is more than circuitous in carcinomas that bear witness a weakened response to anaphase delay signals, termed mitotic slippage [16, 26]. Mitotic slippage and alterations in the master detection of kinetochore zipper defects would increase the number of DSB, adding pressure to the detection and repair pathway. Although the intermission repair pathway might be activated by uncorrected merotelic attachments and the associated Deoxyribonucleic acid impairment, it would exist ineffective in mitosis if a downstream anaphase delay signal is dumb or bypassed.

Figure 2

Signaling by spindle attachment defects. Two independent pathways act to filibuster anaphase. The spindle zipper pathway senses kinetochore tension and is especially efficient for detecting monotelic and syntelic attachments, and the DNA impairment pathway acts as an boosted mechanism that responds to DSB generated by merotelic attachments. When kinetochore attachment defects are undetected, for example in tumors with a CIN phenotype (grey), merotelic attachments and DSB increase, leading to activation of the DNA harm pathway and ultimately to mitotic slippage.

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How cells handle chromosome breaks in mitosis

Although merotelic attachments are processed past diverse pathways, a small proportion escapes detection [21], leaving the daughter cells to deal with a fragmented chromosome. Relaxation of the spindle checkpoint exacerbates this trouble [13], placing additional force per unit area on Deoxyribonucleic acid intermission repair in CIN tumors. In mammalian cells, double-strand breaks are repaired by two major processes, termed non-homologous terminate joining and homologous recombination [34]. The availability of repair pathways at the time and subcellular location of intra-mitotic DSB has important consequences; whereas non-homologous terminate joining repairs breaks past simple religation of two DNA ends, homologous recombination depends on a homologous Dna template. This means that non-homologous finish joining can repair DSB throughout the prison cell cycle, but homologous recombination is nearly inactive in the G1 phase [35]. The Deoxyribonucleic acid breaks caused by uncorrected merotelic attachments are physically the same as other DSB and their centromeric location does non in itself hinder efficient repair [36], but the cell wheel stage in which they are formed obliges the cell to correct Deoxyribonucleic acid impairment during or right after mitosis. In addition, some chromosome fragments are sequestered in micronuclei [13], resulting in physical separation from the remainder of chromosomes and precluding homologous recombination.

Mice deficient in any of the DSB repair proteins are generally hypersensitive to induced Dna damage, although they are usually viable [37, 38]. Whereas not-homologous end joining or homologous recombination repair mutants have problems repairing induced DSB, the inactivation of a single repair pathway does non result in spontaneous DSB accumulation [13, 39, twoscore]. The absence of spontaneous Dna damage in mice defective a single repair pathway implies that the endogenous DSB formation rate must be relatively low or at least is not life threatening. Notwithstanding the low frequency of spontaneous DSB, many tumors evidence increased repair system activeness, in particular that of non-homologous finish joining [41–43]. Non-homologous end joining activation in cancer indicates that DSB are generated at an increased rate, possibly due to chromosome segregation errors and concomitant chromosome arm breakage.

Not-homologous end joining is essential in a CIN background

Non-homologous terminate joining appears to be especially important when spindle checkpoint command is relaxed, because the increase in uncorrected merotelic attachments could promote chromosome breakage. In non-homologous end joining, Ku80 is essential for recruitment of repair complexes to DSB, whereas DNA-PKcs is the principal repair kinase [44]. Although residuum non-homologous terminate joining takes place in both Ku80- and DNA-PKcs-deficient cells, Ku80 mutation has a far greater touch on on DSB repair kinetics than DNA-PKcs mutation [45–47]; Deoxyribonucleic acid-PKcs disruption thus produces a milder phenotype than Ku80 inactivation. Targeted disruption of the death inducer obliterator (Dido) gene, which causes centrosome amplification and spindle checkpoint relaxation [48], results in a CIN phenotype that includes aneuploidy and chromosome breakage [xiii]. To determine whether non-homologous finish joining is essential in a CIN background, we crossed Dido and Ku80 heterozygous mice, interbred the double heterozygotes and genotyped all offspring. Dido and Deoxyribonucleic acid-PKcs heterozygous mice were interbred in the aforementioned way. In our crosses, heterozygous and wild-type pups were born at frequencies compatible with normal Mendelian inheritance; we found slightly fewer Ku80 and Dido mutant newborns (Tabular array 1). In over 1000 pups tested, however, we identified no Dido Ku80 double mutants. When double heterozygous Dido Deoxyribonucleic acid-PKcs mice were crossed, Dido mutants and Dido DNA-PKcs double mutants were built-in at frequencies beneath the expected ratio, only no marked effect of DNA-PKcs mutation was found (Table 2). Although the frequency of Ku80 mutants was reduced, some Dido Ku80 double mutants would be expected; the absence of these double mutant mice thus indicates synthetic lethality, in accordance with the reported intra-mitotic DSB in the Dido mutant [13]. Mutation of Ku80 has a far greater impact on DSB repair kinetics than that of DNA-PKcs in models of induced DNA damage [49, 50], and DNA-PKcs besides appears to exist less important than Ku80 in the repair of DSB generated by uncorrected merotelic attachments.

Tabular array 1 Combined disruption of Dido and Ku80 is embryonic lethal.

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Table two Combined disruption of Dido and Dna-PKcs.

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Since Dido Ku80 double mutant embryos die in utero, nosotros established the time of gestation at which death occurs. Double heterozygous Dido Ku80 mice were interbred and embryos analyzed by dark field microscopy at diverse times postcoitum. Mutant embryo evolution was not markedly different from that of heterozygous counterparts up to E8.five (not shown). Growth filibuster in Dido Ku80 double mutant embryos was beginning credible at E9.5, with underdeveloped head, heart and somites (Fig. 3). At E10.five, Dido and Ku80 single mutant embryos continued to develop unremarkably, whereas most Dido Ku80 double mutant embryos had died and were being reabsorbed, and none survived beyond E12.five. Due to variation in survival, we were unable to define an verbal time point of death. These data nonetheless bear witness that Dido Ku80 double mutant embryos die in utero at mid-gestation, suggesting a role for not-homologous finish joining in the repair of Dna damage generated by uncorrected merotelic attachments.

Effigy 3

Combined disruption of Ku80 and Dido is lethal in mid-gestation. The figure shows embryos isolated at embryonic day E9.v (top) and E10.5 (bottom). Ku80 heterozygous Dido mutant embryos are shown at left and Ku80 Dido double mutant embryos at correct. At E9.5, double mutant embryos show growth delay in head, heart, and somites. At E10.v, most Ku80 Dido double mutant embryos are being resorbed. Magnification, twoscore-fold. All animal experiments were performed in compliance with EU and CNB animate being committee directives.

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Endmost remarks

Merotelic kinetochore attachments seem to be the Achilles' heel of mammalian cell division, as they tin can bring most potentially dangerous genomic instability just are poorly recognized by the spindle checkpoint. Even in normal cells, a minor proportion of cell divisions thus requite ascent to chromosome breakage [21]. In the case of intramitotic chromosome breakage, DSB repair systems could transmit a 2d signal in an effort to delay mitosis progression [28–30]. The combination of signals involved in the detection of spindle errors has important consequences for cancer development, and gives ascent to a working model of early on tumorigenesis (Fig. 4).

Figure four

Model for amplification of chromosomal instability by Dna damage. Initial merotelic attachments activate DNA harm signaling and inhibit prison cell proliferation through anaphase filibuster and induction of apoptosis or senescence. To overcome the block, the downstream spindle checkpoint is suppressed in CIN tumors, increasing the frequency of spindle zipper errors. Equally a side issue of this continuous breakage, Dna repair mechanisms remain activated, leading ultimately to adaptation through suppression of apoptosis and senescence and through spindle checkpoint relaxation (dashed lines).

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Any minor alteration in spindle regulation could event in an increase in merotelic attachments that escape detection, giving ascent to aneuploidy and chromosome breakage [xiii]. Breakage activates cellular Deoxyribonucleic acid damage command, shown by increased DSB repair in many tumors [41–43]. The need for non-homologous stop joining in a CIN groundwork is emphasized past the synthetic lethality of Dido Ku80 double mutants. DNA harm signaling provides feedback to the spindle checkpoint and delays mitosis progression, which prolongs the time window for repair and prevents aneuploidy. Repair by non-homologous cease joining not but limits Dna damage and promotes cell survival, only also catalyzes the fusion of reactive chromosome ends. A chromosome fragment generated past spindle defects can thus form end-to-end fusions with normal chromosomes and initiate the breakage-fusion-span cycle [18]. Once the breakage-fusion-span cycles commence, restoring spindle command no longer ensures stability, since dicentric chromosomes formed past end-to-cease fusions can break, even though private kinetochores are correctly attached [17, eighteen]. A long term effect of Dna damage is cell immortalization; sustained breaks exert selective pressure to evade apoptosis and senescence [51]. Since DSB prevent the progression of mitosis, it is probable that sustained breaks besides facilitate mitotic checkpoint relaxation. Continuous mitotic chromosome breakage could thus explain why, over time, CIN tumors become more cancerous and refractory to treatment. In conclusion, nature's use of DSB repair systems as a fill-in for the detection of merotelic attachments might in fact promote chromosomal instability and act as a motor for carcinogenesis. CIN tumors show precisely the characteristics predicted by the above model: Nigh carcinomas testify chromosomal instability and reduced command of the mitotic spindle, combined with enhanced DNA damage repair and reduced apoptotic potential. The claiming for cancer treatment will be to break this savage circle without causing additional genomic instability.

Abbreviations

CIN:

chromosomal instability

DSB:

double strand Deoxyribonucleic acid break.

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Acknowledgements

The authors thank Dr. Maria Blasco for Ku80 and Dna-PKcs mutant mice, and Catherine Mark for editorial aid. The publication costs for this manuscript were financed by grant PS09/00572 (Fondo de Investigación en Salud) and the experimental work by grant Southward-BIO-0189-2006 (Comunidad Autonoma de Madrid). The Department of Immunology and Oncology was founded and is supported by the Spanish National Research Council (CSIC) and by Pfizer.

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1. Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Darwin 3, UAM Campus Cantoblanco, 28049, Madrid, Espana

   Astrid Alonso Guerrero, Carlos Martínez-A & Karel HM van Wely

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Correspondence to Karel HM van Wely.

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Competing interests

The authors declare that they have no competing interests.

Authors' contributions

AAG performed experiments and analyzed data, CMA designed experiments, KvW wrote the newspaper. All authors read and approved the manuscript.

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Guerrero, A.A., Martínez-A, C. & van Wely, Grand.H. Merotelic attachments and non-homologous end joining are the basis of chromosomal instability. Cell Div 5, thirteen (2010). https://doi.org/10.1186/1747-1028-5-thirteen

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• Received: eighteen April 2010

• Accepted: 17 May 2010

• Published: 17 May 2010

• DOI : https://doi.org/10.1186/1747-1028-5-13

Keywords

• Chromosome Segregation
• Chromosomal Instability
• Chromosome Breakage
• Spindle Checkpoint
• Mitotic Checkpoint

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Source: https://celldiv.biomedcentral.com/articles/10.1186/1747-1028-5-13

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