Merotelic kinetochore orientation occurs frequently during early mitosis in mammalian tissue cells and error correction is achieved by two different mechanisms

Cimini, Daniela; Moree, Ben; Canman, Julie C.; Salmon, Edward D.

doi:10.1242/jcs.00716

Cited by 249 publications

(331 citation statements)

References 54 publications

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“…MCAK inhibition results in merotelic attachments of kinetochores , which may reduce the number of MTs per K-fiber either directly by error correction mechanisms contributing to the release of kinetochore-MTs, or by the aberrant binding sites caused by the merotelic attachments (Cimini et al, 2003;Salmon et al, 2005), which may limit the number of end-on binding sites for MTs. The reduction in interkinetochore distance is consistent with our previous findings (KlineSmith et al, 2004), but different from that reported by others .…”

Section: Control Of Kinetochore Mt Dynamicsmentioning

confidence: 99%

MCAK and Paclitaxel Have Differential Effects on Spindle Microtubule Organization and Dynamics

Rizk

Bohannon

Wetzel

et al. 2009

MBoC

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Within the mitotic spindle, there are multiple populations of microtubules with different turnover dynamics, but how these different dynamics are maintained is not fully understood. MCAK is a member of the kinesin-13 family of microtubule-destabilizing enzymes that is required for proper establishment and maintenance of the spindle. Using quantitative immunofluorescence and fluorescence recovery after photobleaching, we compared the differences in spindle organization caused by global suppression of microtubule dynamics, by treating cells with low levels of paclitaxel, versus specific perturbation of spindle microtubule subsets by MCAK inhibition. Paclitaxel treatment caused a disruption in spindle microtubule organization marked by a significant increase in microtubules near the poles and a reduction in K-fiber fluorescence intensity. This was correlated with a faster t 1/2 of both spindle and K-fiber microtubules. In contrast, MCAK inhibition caused a dramatic reorganization of spindle microtubules with a significant increase in astral microtubules and reduction in K-fiber fluorescence intensity, which correlated with a slower t 1/2 of K-fibers but no change in the t 1/2 of spindle microtubules. Our data support the model that MCAK perturbs spindle organization by acting preferentially on a subset of microtubules, and they support the overall hypothesis that microtubule dynamics is differentially regulated in the spindle. INTRODUCTIONThe cytoskeleton must undergo dramatic reorganization as cells transition from interphase to mitosis to assemble the mitotic spindle. The spindle is a macromolecular structure composed of a dynamic array of microtubules (MTs) and their associated proteins that is necessary for proper chromosome segregation (Compton, 2000;Walczak and Heald, 2008). At the onset of mitosis, there is an increase in MT turnover that allows for breakdown of the interphase array and assembly of the mitotic spindle (Saxton et al., 1984;. This change is correlated with an increased catastrophe frequency (transition from growth to shrinkage) and a decreased rescue frequency (transition from shrinkage to growth) (Belmont et al., 1990;Gliksman et al., 1992;Verde et al., 1992;Rusan et al., 2001). The changes in MT dynamics are also correlated with a change in MT polymer levels during mitosis (Zhai et al., 1996). At nuclear envelope breakdown, there is a dramatic decrease in MT polymer levels, which may allow the cell to rapidly assemble a mitotic spindle because the released tubulin dimers can polymerize into new spindle MTs. As the cell progresses from mitosis to the next interphase, there is no change in the levels of MT polymer (Zhai et al., 1996), suggesting that MT polymer gets reorganized to reform the interphase MT cytoskeleton, without a significant change in the dynamics of the MTs. These studies highlight the need for the cell to possess a mechanism to temporally regulate MT dynamics.In addition to the temporal changes in dynamics throughout the cell cycle, the dynamics of MTs within mitosis are also...

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Section: Control Of Kinetochore Mt Dynamicsmentioning

confidence: 99%

MCAK and Paclitaxel Have Differential Effects on Spindle Microtubule Organization and Dynamics

Rizk

Bohannon

Wetzel

et al. 2009

MBoC

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“…Merotelic attachments form transiently in all cells (Cimini et al, 2003) (reviewed by Cimini and Degrassi, 2005;Musacchio and Salmon, 2007), but in normal conditions they are resolved by a specific pathway requiring Aurora-B and MCAK (Hauf et al, 2003;Kline-Smith et al, 2003;Knowlton et al, 2006). In RANBP1-depleted cultures, the increased frequency of lagging chromosomes and micronuclei in anaphase/telophase, with no detectable abnormalities in metaphase and an intact checkpoint response to NOC, would be compatible with an increased Journal of Cell Science 120 (21) frequency of merotelic attachments.…”

Section: Ranbp1-interfered Cells Display Segregation Defects During Mmentioning

confidence: 99%

RANBP1 localizes a subset of mitotic regulatory factors on spindle microtubules and regulates chromosome segregation in human cells

Tedeschi

Ciciarello

Mangiacasale

et al. 2007

Journal of Cell Science

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The GTPase RAN has an established role in spindle assembly and in mitotic progression, although not all mechanisms are fully understood in somatic cells. Here, we have downregulated RAN-binding protein 1 (RANBP1), a RAN partner that has highest abundance in G2 and mitosis, in human cells. RANBP1-depleted cells underwent prolonged prometaphase delay often followed by apoptosis. Cells that remained viable assembled morphologically normal spindles; these spindles, however, were hyperstable and failed to recruit cyclin B1 or to restrict the localization of HURP (DLG7), a microtubule-stabilizing factor, to plus-ends. RANBP1 depletion did not increase the frequency of unattached chromosomes; however, RANBP1-depleted cells frequently showed lagging chromosomes in anaphase, suggesting that merotelic attachments form and are not efficiently resolved. These data indicate that RANBP1 activity is required for the proper localization of specific factors that regulate microtubule function; loss of this activity contributes to the generation of aneuploidy in a microtubule-dependent manner.

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“…In addition, evidence from budding yeast would suggest that syntelic attachments can be detected by the mitotic spindle checkpoint. 24 Finally, merotelic attachments occur frequently in early mitosis 25 and are not detected by the spindle checkpoint. [26][27][28][29][30][31] Nevertheless, many of them are corrected before anaphase onset by an Aurora B-dependent mechanism, 25,32 as discussed later.…”

Section: Kinetochore-microtubule Attachment and Accuracy Of Chromosommentioning

confidence: 99%

“…25,26,29,30 But, when sister chromatids separate at anaphase, opposing pulling forces exerted on merotelic kinetochores by microtubules to opposite poles affect anaphase A poleward movement. 26,27 Movement of merotelically oriented chromosomes away from the equator in anaphase depends on the ratio of kinetochore microtubules to the correct versus incorrect pole.…”

Section: Kinetochore-microtubule Attachment and Accuracy Of Chromosommentioning

confidence: 99%

“…The cell possesses a merotelic kinetochore (arrow) that appears tilted as compared to normally attached kinetochores. Adapted from Cimini et al 25 (B) Live PtK1 cell microinjected with X-Rhodamine-labeled tubulin (red, microtubule labeling) and Alexa 488-labeled anti-CENP-F antibodies (green, kinetochore and spindle pole labeling). The cell possesses a merotelic kinetochore (arrow) that appears clearly tilted as compared to all the other correctly attached kinetochores.…”

Section: How Does Aurora B Detect Kinetochore-microtubule Mis-attachmmentioning

confidence: 99%

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Detection and Correction of Merotelic Kinetochore Orientation by Aurora B and its Partners

Cimini

2007

Cell Cycle

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Merotelic kinetochore orientation is a kinetochore-microtubule mis-attachment in which a single kinetochore binds microtubules to both spindle poles, rather than just one. Merotelic attachments occur frequently in early mitosis and can induce anaphase lagging chromosomes and aneuploidy if not corrected before anaphase onset. Merotelic kinetochore orientation does not interfere with chromosome alignment at the metaphase plate and does not activate the mitotic spindle checkpoint. However, a correction mechanism for merotelic attachment reduces the number of merotelic kinetochores entering anaphase, thus preventing chromosome mis-segregation. Results from many different studies support the idea that Aurora B kinase plays a critical role in this merotelic correction mechanism by phosphorylating key substrates at the kinetochore and promoting turnover of kinetochore microtubules. In addition, recent studies are starting to identify the possible 'sensors' of the system that would be able to detect the mis-attachment and communicate this to Aurora B. Here, I review these studies and discuss a model for how merotelic kinetochore orientation could be detected and corrected before anaphase onset.

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Merotelic kinetochore orientation occurs frequently during early mitosis in mammalian tissue cells and error correction is achieved by two different mechanisms

Abstract: SummaryMerotelic kinetochore orientation occurs frequently during early mitosis in mammalian tissue cells and error correction is achieved by two different mechanisms

Cited by 249 publications

References 54 publications

MCAK and Paclitaxel Have Differential Effects on Spindle Microtubule Organization and Dynamics

MCAK and Paclitaxel Have Differential Effects on Spindle Microtubule Organization and Dynamics

RANBP1 localizes a subset of mitotic regulatory factors on spindle microtubules and regulates chromosome segregation in human cells

Detection and Correction of Merotelic Kinetochore Orientation by Aurora B and its Partners

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