Aneuploidy in mitosis of PtK1 cells is generated by random loss and nondisjunction of individual chromosomes

Torosantucci, Liliana; Puzzonia, Marco De Santis; Cenciarelli, Chiara; Rens, Willem; Degrassi, Francesca

doi:10.1242/jcs.047944

Cited by 24 publications

(22 citation statements)

References 45 publications

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“…Thus, chromosomes that lag in anaphase tend not to missegregate (i.e., cause nondisjunction) in human cells. These results are in agreement with data from nonhuman model cell systems showing that lagging chromosomes rarely missegregate (19,20).…”

Section: Discussionsupporting

confidence: 91%

Chromosome missegregation in human cells arises through specific types of kinetochore–microtubule attachment errors

Thompson

Compton

2011

Proc. Natl. Acad. Sci. U.S.A.

247

225

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Most solid tumors are aneuploid, and many missegregate chromosomes at high rates in a phenomenon called chromosomal instability (CIN). CIN reflects the erosion of mitotic fidelity, and it correlates with poor patient prognosis and drug resistance. The most common mechanism causing CIN is the persistence of improper kinetochore-microtubule attachments called merotely. Chromosomes with merotelic kinetochores often manifest as lagging chromosomes in anaphase, suggesting that lagging chromosomes fail to segregate properly. However, it remains unknown whether the lagging chromosomes observed in anaphase segregate to the correct or incorrect daughter cell. To address this question, we tracked the segregation of a single human chromosome during cell division by using LacI-GFP to target an integrated LacO array. By scoring the distribution of each sister chromatid during mitosis, we show that a majority of lagging chromosomes in anaphase segregate to the correct daughter cell. Instead, sister chromatids that segregate erroneously frequently do so without obvious evidence of lagging during anaphase. This outcome is expected if sister kinetochores on a chromosome bind microtubules oriented toward the same spindle pole, and we find evidence for syntelic kinetochore attachments in cells after treatments that increase missegregation rates. Thus, lagging chromosomes in anaphase are symptomatic of defects in kinetochore-microtubule attachment dynamics that cause chromosome missegregation associated with CIN, but the laggards rarely missegregate.aneuploidy | syntely | MCAK | micronuclei | genome instability S olid tumors are frequently aneuploid and many missegregate chromosomes at high rates in a phenomenon called chromosomal instability (CIN; refs. 1 and 2). CIN is associated with poor patient prognosis, and various studies have shown that it correlates with advanced tumor stage including acquisition of metastatic potential and drug resistance (3-5). It has been proposed that by frequently changing the karyotype of tumor cells, that CIN provides an agent of change that drives the evolution of tumor cell phenotypes (3-8). The treatment difficulties encountered in advanced stage tumors underscores the importance of determining the mechanisms of CIN and how they contribute to tumor growth.Various mechanisms have been proposed to cause CIN including dysfunction of the spindle assembly checkpoint, defects in sister chromatid cohesion, and defects in the attachment of chromosomes to spindle microtubules (2). Recently, live cell imaging demonstrated that the most common cause of CIN is the persistence of errors in the attachment of spindle microtubules to chromosomes (9, 10). Microtubules bind to chromosomes at specialized structures called kinetochores. Each chromosome has a pair of kinetochores, and faithful chromosome segregation arises when single kinetochores bind microtubules oriented toward only one spindle pole resulting in the biorientation of chromosomes on the spindle. However, errors in the orientation of kinetochore-mic...

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Section: Discussionsupporting

confidence: 91%

Chromosome missegregation in human cells arises through specific types of kinetochore–microtubule attachment errors

Thompson

Compton

2011

Proc. Natl. Acad. Sci. U.S.A.

247

225

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“…To determine whether lagging chromosomes lead to the uneven segregation phenotype, we analyzed chromosome segregation in mde4 Δ mutants expressing histone-mRFP using time-lapse analysis. We observed that 46% (30/65) of mde4 Δ cells that display lagging chromosomes in anaphase show uneven chromosome segregation in telophase, indicating that some but not all lagging chromosomes lead to segregation errors consistent with other studies [8–10]. However, because all cases (n=30) of uneven chromosome segregation appeared to be the result of earlier improper segregation of anaphase lagging chromosomes (for example see Movie S1), we combined the two classes (lagging (anaphase) and unevenly segregated (telophase) chromosomes) for subsequent analysis of fixed mde4 Δ and swi6 Δ cells.…”

Section: Resultssupporting

confidence: 91%

A Role for Metaphase Spindle Elongation Forces in Correction of Merotelic Kinetochore Attachments

Choi

McCollum

2012

Current Biology

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Summary During mitosis equal segregation of chromosomes depends on proper kinetochore–microtubule attachments. Merotelic kinetochore orientation, in which a single kinetochore binds microtubules from both spindle poles [1], is a major cause of chromosome instability [2], which is commonly observed in solid tumors [3, 4]. Using the fission yeast Schizosaccharomyces pombe we show that a proper force balance between kinesin motors on interpolar spindle microtubules is critical for correcting merotelic attachments. Inhibition of the plus end directed spindle elongation motors kinesin-5 (Cut7) and kinesin-6 (Klp9) reduces spindle length, tension at kinetochores, and the frequency of merotelic attachments. In contrast, merotely is increased by deletion of the minus end directed kinesin-14 (Klp2) or overexpression of Klp9. Also, Cdk1 regulates spindle elongation forces to promote merotelic correction by phosphorylating and inhibiting Klp9. The role of spindle elongation motors in merotelic correction is conserved since partial inhibition of the human kinesin-5 homolog Eg5 using the drug monastrol reduces spindle length and lagging chromosome frequency in both normal (RPE-1) and tumor cells (CaCo-2). These findings reveal unexpected links between spindle forces and correction of merotelic attachments and show that pharmacological manipulation of spindle elongation forces might be used to reduce chromosome instability in cancer cells.

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“…Through persistent chromosome shuffling, tumor cells with CIN continuously sample the genetic landscape with an almost limitless number of combinations, based on evidence in vertebrate cells that all chromosomes have an equal probability for mis-segregation [124]. Whereas some chromosome combinations may provide no selective advantage or a disadvantage, others could provide growth advantages to cells in the tumor microenvironment, particularly under the selective pressure applied by chemotherapy.…”

Section: Cin As a Target For Cancer Therapymentioning

confidence: 99%

Mechanisms of Chromosomal Instability

2010

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Most solid tumors are aneuploid, having a chromosome number that is not a multiple of the haploid number, and many frequently mis-segregate whole chromosomes in a phenomenon called chromosomal instability (CIN). CIN positively correlates with poor patient prognosis, indicating that reduced mitotic fidelity contributes to cancer progression by increasing genetic diversity among tumor cells. Here, we review the mechanisms underlying CIN, which include defects in chromosome cohesion, mitotic checkpoint function, centrosome copy number, kinetochore–microtubule attachment dynamics, and cell-cycle regulation. Understanding these mechanisms provides insight into the cellular consequences of CIN and reveals the possibility of exploiting CIN in cancer therapy.

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Aneuploidy in mitosis of PtK1 cells is generated by random loss and nondisjunction of individual chromosomes

Cited by 24 publications

References 45 publications

Chromosome missegregation in human cells arises through specific types of kinetochore–microtubule attachment errors

Chromosome missegregation in human cells arises through specific types of kinetochore–microtubule attachment errors

A Role for Metaphase Spindle Elongation Forces in Correction of Merotelic Kinetochore Attachments

Mechanisms of Chromosomal Instability

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