Merotelic kinetochore attachment: causes and effects

Gregáň, Juraj; Poláková, Silvia; Zhang, Lijuan; Tolić, Iva Marija; Cimini, Daniela

doi:10.1016/j.tcb.2011.01.003

Cited by 222 publications

(228 citation statements)

References 96 publications

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“…Importantly, we have found that also wild-type MII oocytes frequently display merotelic attachments at the metaphase stage, as well as lagging chromosomes at anaphase onset. This strongly suggests that merotelic attachments contribute significantly to chromosome mis-segregation in wild-type female germ cells, similar to what previously been documented for somatic cells during mitosis 10,11,27 . In conclusion, our results show that merotely contributes to aneuploidy in mammalian oocytes.…”

Section: Discussionsupporting

confidence: 86%

“…We found that chromosomes at the spindle equator displayed an amphitelic configuration (Fig. 1e), a geometric orientation promoted by opposing end-on microtubule attachments to the sister kinetochores of chromosomes [10][11][12] . Occasionally, one of the two sister kinetochores of chromosomes were bi-directionally attached to microtubules, suggesting also the presence of merotelic attachments ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 87%

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Merotelic attachments allow alignment and stabilization of chromatids in meiosis II oocytes

2014

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The chromosome segregation process in human oocytes is highly error-prone, generating meiosis II (MII) oocytes with unbalanced chromatids that contribute to aneuploidy in offspring. This raises questions regarding the mechanism for transmission of chromatids and how chromatids evade the error correction mechanisms in MII oocytes. Here, we analyse the behaviour of chromatids in mouse MII oocytes. We find that chromatids align at the spindle equator at the metaphase stage of MII and that their presence does not obstruct entry into the anaphase stage. The alignment process is mediated by merotelic (bi-directional) microtubule-kinetochore attachments, revealing a multi-domain organization of the kinetochore of mammalian meiotic chromosomes. Our results suggest that biorientation of chromatids stabilize microtubule attachments at the kinetochores in a tension-dependent manner. Our results also suggest that merotelic attachments contribute to chromosome mis-segregation in wild-type MII oocytes. Thus, merotely is an important promoter of aneuploidy in mammalian oocytes.

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Section: Discussionsupporting

confidence: 86%

Section: Resultsmentioning

confidence: 87%

Merotelic attachments allow alignment and stabilization of chromatids in meiosis II oocytes

2014

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“…However, the process of centrosome clustering produces many merotelic kinetochore-microtubule attachments, where a kinetochore attaches to microtubules emanating from both spindle poles. Chromosomes with merotelic attachments are frequently mis-segregated (35). It is difficult to imagine that the liver culls the appreciable fraction of aneuploid hepatocytes expected to arise from these faulty mitoses.…”

Section: Discussionmentioning

confidence: 99%

Single cell sequencing reveals low levels of aneuploidy across mammalian tissues

Knouse

Whittaker

et al. 2014

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

281

253

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Significance Aneuploidy refers to the gain or loss of individual chromosomes within a cell. Typically, aneuploidy is associated with detrimental consequences at both the cellular and organismal levels. However, reports of high levels of aneuploidy in the brain and liver suggested that aneuploidy might play a positive role in these organs. Here we use single cell sequencing to determine the prevalence of aneuploidy in somatic tissues. We find that aneuploidy is a rare occurrence in the liver and brain and is no more prevalent in these tissues than in skin. Our results demonstrate high karyotypic stability in somatic tissues, arguing against a role for aneuploidy in organ function and reinforcing its adverse effects at the cellular and organismal levels.

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“…[8][9][10][11][12][13][14][15] MPS1 has also been implicated in the so-called 'error correction mechanism', 16 a poorly characterized process that resolves the erroneous KT-MT attachments that frequently form in the early steps of mitosis. 17,18 According to current models, AURKB, one component of the chromosomal passenger complex (reviewed by Ruchaud et al 19 ), catalyzes this process by destabilizing incorrect attachments, hence generating free KTs that activate the SAC. 20,21 Contradictory reports place MPS1 either upstream or downstream of AURKB in this pathway.…”

mentioning

confidence: 99%

Characterization of novel MPS1 inhibitors with preclinical anticancer activity

et al. 2013

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,5,6,11,12,13 Monopolar spindle 1 (MPS1), a mitotic kinase that is overexpressed in several human cancers, contributes to the alignment of chromosomes to the metaphase plate as well as to the execution of the spindle assembly checkpoint (SAC). Here, we report the identification and functional characterization of three novel inhibitors of MPS1 of two independent structural classes, N-(4-{2- [(2-cyanophenyl) and N-cyclopropyl-4-{8-(isobutylamino)imidazo[1,2-a]pyrazin-3-yl}benzamide (Mps-BAY2b) (two imidazopyrazines). By selectively inactivating MPS1, these small inhibitors can arrest the proliferation of cancer cells, causing their polyploidization and/or their demise. Cancer cells treated with Mps-BAY1 or Mps-BAY2a manifested multiple signs of mitotic perturbation including inefficient chromosomal congression during metaphase, unscheduled SAC inactivation and severe anaphase defects. Videomicroscopic cell fate profiling of histone 2B-green fluorescent protein-expressing cells revealed the capacity of MPS1 inhibitors to subvert the correct timing of mitosis as they induce a premature anaphase entry in the context of misaligned metaphase plates. Hence, in the presence of MPS1 inhibitors, cells either divided in a bipolar (but often asymmetric) manner or entered one or more rounds of abortive mitoses, generating gross aneuploidy and polyploidy, respectively. In both cases, cells ultimately succumbed to the mitotic catastrophe-induced activation of the mitochondrial pathway of apoptosis. Of note, low doses of MPS1 inhibitors and paclitaxel (a microtubular poison) synergized at increasing the frequency of chromosome misalignments and missegregations in the context of SAC inactivation. This resulted in massive polyploidization followed by the activation of mitotic catastrophe. A synergistic interaction between paclitaxel and MPS1 inhibitors could also be demonstrated in vivo, as the combination of these agents efficiently reduced the growth of tumor xenografts and exerted superior antineoplastic effects compared with either compound employed alone. Altogether, these results suggest that MPS1 inhibitors may exert robust anticancer activity, either as standalone therapeutic interventions or combined with microtubule-targeting chemicals. Mitosis is a sophisticated process that ensures the faithful inheritance of the genetic material by the cellular progeny while preventing aneuploidy and chromosomal instability (CIN), two established hallmarks of cancer. 1-3 A set of protein kinases that are collectively known as mitotic kinases, including Aurora kinases (AURKs), mitotic cyclin-dependent kinases (CDKs), Polo-like kinases and monopolar spindle 1 (MPS1), regulates and coordinates multiple aspects of chromosome segregation during mitosis. 4 MPS1 (also known as TTK) is a dual-specificity kinase (meaning that it phosphorylates both serine/threonine and tyrosine residues) with an established role in the proper alignment and orientation of chromosomes on the metaphase plate. 5 MPS1 is a core component of the spindle assembl...

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Merotelic kinetochore attachment: causes and effects

Cited by 222 publications

References 96 publications

Merotelic attachments allow alignment and stabilization of chromatids in meiosis II oocytes

Merotelic attachments allow alignment and stabilization of chromatids in meiosis II oocytes

Single cell sequencing reveals low levels of aneuploidy across mammalian tissues

Characterization of novel MPS1 inhibitors with preclinical anticancer activity

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