Cells are able to copy their DNA and then divide to make two daughter cells that each have a complete set of genetic material. In animal cells, the DNA is arranged within structures called chromosomes and groups of proteins called centrosomes control the process that separates the chromosome copies as the cell divides.

Each cell starts off with one centrosome, but before it divides, this centrosome is copied so that the cell now has two centrosomes at opposite ends of the cell, one old and one new. Filaments called microtubules assemble from the centrosomes and attach to the chromosomes. The microtubules first align all the chromosomes in the middle of the cell before pulling them towards the centrosomes as the cell divides.

Some cells divide such that the two daughter cells are destined to take on different roles, for example, a stem cell may divide to produce one stem cell and one skin cell. The end of the dividing cell that will become the stem cell contains the older centrosome, while the half that forms the skin cell will receive the younger centrosome. Other cells in the body may divide to form daughter cells that have the same fate, known as symmetrical division. In these cases, it is thought that there is no difference between the behaviour of the old and young centrosomes, but this idea has never been tested.

Here, Gasic et al. studied symmetrical division of human cells using fluorescent tags that made it possible to tell the centrosomes apart. The experiments show that the microtubules that assemble from the older centrosome bind the chromosome more tightly than those that form from the younger centrosome. This delays the alignment of the chromosomes that are connected to the old centrosome, as this process requires a flexible attachment. Moreover, in case the two chromosome copies fail to separate properly as cells divide, the older centrosome is more likely to receive both chromosome copies at the expense of the other centrosome. A protein called cenexin is present at higher levels around older centrosomes than around younger ones and is responsible for this effect.

Gasic et al.'s findings show that the age of the centrosomes leads to asymmetry in all cell divisions, even those that produce cells that are destined to have the same role in an organism. The next challenge will be to understand whether this asymmetry has any consequences for cells, in particular cancer cells.

The bipolar spindle has a symmetric appearance; nevertheless it contains two centrosomes of different ages, as every centrosome is duplicated once during the cell cycle, resulting in the presence of an old and young centrosome at mitotic onset (Nigg and Stearns, 2011). In asymmetric stem cell divisions centrosome age differentially affects their capacity to nucleate microtubules and their positioning with respect to the polarity and cell division axis (Yamashita et al., 2007; Wang et al., 2009; Januschke et al., 2013). Stem cells stereotypically inherit the centrosome, which nucleates more microtubules, which in most cases is the old centrosome (except in fly neuroblast divisions, where stem cells retain the young active centrosome; Januschke et al., 2011, Conduit and Raff, 2010). Old centrosomes also co-segregate with the ciliary membrane in stem cell divisions, allowing daughter stem cells to form a primary cilium earlier than the differentiating daughter cells (Paridaen et al., 2013). In symmetric divisions, the old and young centrosomes can be differentiated at the ultra-structural level, and in terms of their microtubule-anchoring capacity during interphase (Rieder and Borisy, 1982; Piel et al., 2000). The oldest centriole within the old centrosome contains distal and subdistal appendages: the first are necessary for centrioles to become basal bodies that can contact the plasma membrane (Graser et al., 2007; Hoyer-Fender, 2010), while the latter are involved in the organization of the interphase microtubule network, due to the presence of ninein, a key microtubule-anchoring protein (Mogensen et al., 2000). Both structures require the presence of cenexin, the oldest known marker for old centrosomes and appendages (Lange and Gull, 1995; Ishikawa et al., 2005). Importantly, all these structural differences disappear progressively as cells enter mitosis; therefore, it is assumed that the old and the young centrosomes behave indistinguishably in symmetrically dividing cells, resulting in a symmetric bipolar spindle. This hypothesis has, however, never been directly tested at the functional level. Here, we tested whether centrosome age affects cell division in symmetrically dividing human cells, focusing on the ability of centrosomes to organize the alignment and segregation of sister-chromatids into two daughter cells.

The first key task of the mitotic spindle is to bind to chromosomes via kinetochores and align them onto the metaphase plate (Kops et al., 2010). To distinguish between old and young centrosomes, we used untransformed hTert-RPE1 and transformed HeLa cell lines expressing eGFP-centrin1, a centriolar protein whose abundance correlates with centriole age, or an anti-cenexin antibody, a marker for old centrosomes (Figure 1A,B, Kuo et al., 2011; Lange and Gull, 1995). In the vast majority of the cases both markers were enriched at the same centriole pair, indicating a robust recognition of the old centrosomes (data not shown). To investigate whether half-spindles associated with old or new centrosomes align chromosomes with the same efficiency, we analyzed late prometaphase cells that contained few unaligned chromosomes. We found that 61.23% of the unaligned chromosomes were in the vicinity of old centrosomes in Hela-eGFP-centrin1 cells as opposed to 50% expected for an unbiased distribution, suggesting a difference in the efficiency of chromosome alignment (Figure 1C,D, statistical tests for the chromosome alignment assays throughout the study are shown in Table 1). As such unaligned chromosomes were rare, we also treated cells with 10 ng/ml nocodazole, a condition that moderately stabilizes microtubules (Vasquez et al., 1997), and that delays chromosome alignment, leading to 3–6 unaligned chromosomes per cell (Figure 1C). Unaligned chromosomes were again preferentially found in the vicinity of the old centrosomes in HeLa eGFP-centrin1 (63.9%) and hTert-RPE1-eGFP-centrin1 cells (71.8%), confirming the bias in chromosome alignment (Figure 1E). We found the same bias (67.8%) in wild-type nocodazole-treated hTert-RPE1 cells stained with cenexin, excluding any effect due to eGFP-centrin1 expression (Figure 1E). We conclude that the half-spindles associated to the old centrosomes accumulate more unaligned chromosomes or that unaligned chromosomes align less efficiently when bound to microtubules emanating from the old centrosomes.

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The bias in unaligned chromosomes could reflect faster kinetics in the initial capture of sister-kinetochore pairs by old centrosomes, for example, because they are closer to kinetochores at nuclear envelope breakdown or because they mature—that is, acquire a high, mitotic microtubule-nucleating capacity—earlier. Alternatively, the bias could reflect a permanent difference between the two centrosomes to capture or to align chromosomes. To test whether at mitotic onset old centrosomes capture kinetochores faster because they are closer, we compared the distances between kinetochores and old and young centrosomes at mitotic onset, but found no difference (Figure 2A). We next forced hTert-RPE1 or HeLa cells to enter mitosis with monopolar spindles by treating them with monastrol, a reversible inhibitor of Eg5, the kinesin that separates centrosomes (Mayer et al., 1999). A monastrol washout led to bipolar spindles with few unaligned chromosomes, 74.4% of which were adjacent to old centrosomes, indicating that the bias is independent of the initial centrosome position (Figure 2B,C; and Figure 2—figure supplement 1). To test whether old centrosomes capture more kinetochores because they mature earlier, we treated cells with high doses of nocodazole (1 μg/ml), allowing them to enter mitosis without microtubules and to fully mature the two centrosomes (Khodjakov and Rieder, 1999), before washing out nocodazole for 1 hr: 62.6% of the unaligned chromosomes were adjacent to old centrosomes, indicating that the alignment bias reflects a permanent difference between the centrosomes that is independent of the initial conditions at mitotic onset (Figure 2B,C). The two washout experiments also confirmed that this bias does not require low nocodazole concentrations, since in both cases, cells were released in nocodazole-free medium.

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In asymmetric cell divisions the old and young centrosomes have different capacities to nucleate microtubules, providing a key clue for centrosome positioning and inheritance (Wang et al., 2009; Januschke et al., 2013; Lerit and Rusan, 2013). If microtubule nucleation from the two centrosomes also differed in symmetric cell division, this might allow one centrosome to capture more kinetochores. However, a microtubule re-nucleation assay revealed no difference in microtubule nucleation capacity between the two centrosomes in HeLa and RPE1 cells (Figure 2D,E), suggesting that the centrosomal microtubule nucleation capacity did not cause the biased distribution of unaligned chromosomes. To study if chromosome alignment process per se is asymmetric, we inhibited the Centromere-associated Protein E (CENP-E), the kinetochore-bound kinesin that aligns polar chromosomes by transporting them along existing spindle microtubules (Wood et al., 1997; Kapoor et al., 2006; Barisic et al., 2014). Partial CENP-E inhibition, yielding few polar chromosomes, abolished the bias in the distribution of unaligned chromosomes in the absence or presence of 10 ng/ml nocodazole, (Figure 2F,G, 49.87% and 52.29% respectively), indicating that the bias depends on CENP-E, and that chromosome alignment itself is biased by centrosome age.

The CENP-E-dependent alignment bias could be due to an asymmetric abundance of CENP-E; however, the levels of CENP-E on unaligned chromosomes associated to old or young centrosomes were equal (Figure 3A,B and Figure 3—figure supplement 1A). Alternatively, since CENP-E favours lateral kinetochore–microtubule attachments to transport unaligned chromosomes towards the metaphase plate (Kapoor et al., 2006), we reasoned that a difference in the types of kinetochore–microtubule attachments might bias the alignment of unaligned chromosomes: specifically end-on attachments might delay CENP-E driven chromosome alignment, by creating a poleward drag. Indeed, chromosomes that are not captured by microtubules emanating from both poles, bind laterally to microtubules from the closest pole, and are first driven to this pole in a dynein-dependent manner, before CENP-E aligns them on the metaphase plate (Barisic et al., 2014). During these movements, kinetochores can in some cases form end-on monotelic or syntelic attachments. These non-bipolar end-on attachments are normally destabilized in an Aurora-B-dependent manner (Hauf et al., 2003), favouring the formation of lateral kinetochore–microtubule attachments. However, if end-on attachments were to be more stable at one centrosome, they would delay this conversion and create a drag on the CENP-E driven alignment. To test this hypothesis, we visualized by 3D-high-resolution microscopy kinetochore–microtubule attachments of individual, single kinetochores on unaligned chromosomes in cells treated with 10 ng/ml nocodazole and fixed with glutaraldehyde. At old centrosomes nearly three times more individual kinetochores had end-on attachments (13.0% vs 4.7% at the young centrosome, p = 0.003 in paired t-test) and fewer lateral attachments (83.6% vs 89.1% at the young centrosomes; p = 0.0007 in paired t-test; overall p = 0.0024 in 2way-ANOVA-test; Figure 3C,D and Figure 3—figure supplement 2); the number of unattached kinetochores was higher at young centrosomes, even tough this difference was statistically not significant (p = 0.06 in paired t-test; Figure 3—figure supplement 2). This implied an overall higher stability of kinetochore–microtubules at old centrosomes. To confirm this result, we quantified the levels of tubulin acetylation on individual kinetochore–fibres of sister-kinetochore pairs aligned on the metaphase plate, as tubulin acetylation preferentially accumulates on stable microtubules (Webster and Borisy, 1989). This analysis revealed higher level of acetylation on kinetochore–microtubules associated with old centrosomes (median difference of 22% in tubulin acetylation at the plus ends of microtubules attached to sister-kinetochores vs 2% in CREST levels between sister-kinetochores, p < 0.0001 in Wilcoxon Signed Rank Test; Figure 3E,F and Figure 3—figure supplement 1C). In contrast, when we measured the levels of detyrosinated tubulin, a modification that has been linked to preferential CENP-E motor activity (Barisic et al., 2015), we found no difference (median difference of 0.3%; Figure 3F and Figure 3—figure supplement 1D). To also functionally confirm the difference in microtubule stability, metaphase cells were treated for 10 min with 0.5 mM Ca²⁺, a condition that gradually destabilizes microtubules, before fixing them with glutaraldehyde and staining for kinetochores and microtubules. While such a treatment did not reveal strong overall differences in the two half-spindles (Figure 3G), a detailed analysis of kinetochore–microtubule attachments of aligned sister-kinetochores revealed that kinetochores oriented towards young centrosomes were significantly more likely to have lost their attachment, than those oriented towards the old centrosome (56.8% vs 43.2%; p = 0.014 in paired t-test; Figure 3G,H). Together, these data indicated that the kinetochore–microtubules emanating from old centrosomes are more stable.

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To test if the difference in kinetochore–microtubule stability is at the origin of the alignment bias, we depleted the kinetochore proteins Dsn1 or Nnf1 (both Mis12 complex), or treated the cells with a low dose of taxol (5 nM). These conditions strongly destabilize kinetochore–microtubules (Dsn1 and Nnf1 depletion; (Kline et al., 2006), or hyperstabilize kinetochore–microtubules (taxol; Figure 3—figure supplement 3). Either treatment abolished the bias in alignment and equalized the number of end-on attached unaligned kinetochores (Figure 3D,I,J). In contrast, knock-down of the Mitotic Centromere-Associated Kinesin (MCAK), a microtubule depolymerase that is required for destabilization of erroneous kinetochore–microtubule attachments (Knowlton et al., 2006), whose depletion leads to mild microtubule stabilization in metaphase, but not in prometaphase ((Bakhoum et al., 2009) and Figure 3—figure supplement 3), did not change the bias in chromosome alignment (Figure 3I,J). This suggested that a massive stabilization or destabilization of all kinetochore–microtubules equilibrates the difference in kinetochore–microtubule stability and chromosome alignment, but that a mild stabilization does not change this bias. We conclude that the difference in kinetochore–microtubule stability biases chromosome alignment.

Which factors at centrosomes could generate an age-dependent difference in kinetochore–microtubule stability causing a bias in chromosome alignment? We first considered two centrosomal kinases, Aurora-A and Plk1, which can both affect kinetochore–microtubule stability (Liu et al., 2012; Bakhoum et al., 2014). We compared by quantitative immunofluorescence the levels of Plk1 or the activity of Aurora-A (with an antibody that is specific for active Aurora-A) at old and new centrosomes, to reveal a potential asymmetry in kinase levels/activity. While Plk1 was symmetrically distributed, we found a modest increase of active Aurora-A on old centrosomes in HeLa cells (Figure 3K and Figure 3—figure supplement 1B). This difference was, however, not present in RPE1 cells (Figure 3K); moreover inhibition of Aurora-A or Plk1 did not abolish the bias in chromosome alignment, indicating that it does not depend on these two kinases (Figure 3L). In a second step, we investigated the possible involvement of ninein, as it is essential for cell fate determination in asymmetric cell divisions of neuronal progenitors and preferentially localizes to old centrosomes in asymmetric cell division (Wang et al., 2009), and of cenexin itself, the classical marker for old centrosomes (Figure 3K—note that ninein levels could not be compared on old and young mitotic centrosomes, as it is only present at very low levels (Logarinho et al., 2012)). While ninein depletion had no effect on chromosome alignment, cenexin depletion randomized the distribution of unaligned chromosomes (Figure 3I,J). Furthermore, it also equalized the percentage of end-on attached kinetochores at unaligned chromosomes, indicating that cenexin affects kinetochore–microtubule stability (Figure 3D). We conclude that old centrosomes stabilize kinetochore–microtubules in a cenexin-dependent manner.

The ultimate function of the mitotic spindle is to accurately segregate sister chromatids. If kinetochore–microtubules bound to the old centrosomes were more stable, we predicted that this should affect the fate of chromosomes that fail to fully disjoin in anaphase; chromosome non-disjunction is a frequent cause of chromosome mis-segregation in cancer cells, that can be caused by various defects, such as stretches of unreplicated DNA, telomere fusions, or chromosome entanglements (Aguilera and García-Muse, 2013). To monitor the fate of such chromosome non-disjunction, we monitored by live-cell imaging HeLa-eGFP-centrin1/mCherry-CENP-A cells released for synchronization purpose from a monastrol arrest. As previously reported, this procedure produced a number of single lagging, most likely merotelic, kinetochores, whose exact fate could not be tracked. However, in addition in roughly 2–5% of anaphases, we observed the presence of two lagging kinetochores that moved in synchrony between the two daughter DNA masses, but were separated by several microns, suggesting a sister-kinetochore pair on a non-disjoint chromosome (Figure 4A and Video 1). This assumption was confirmed by high-resolution immunofluorescence imaging, as such kinetochore pairs were invariably connected by a DNA thread (see representative images in Figure 4B). In those instances where both sister-kinetochores segregated to the same daughter cell, we found a strong bias in chromosome mis-segregation as 18 out of the 21 analyzed kinetochore pairs co-segregated with the old centrosome (Figure 4C; Video 1; number of experiments, cells and statistical tests for all chromosome mis-segregation events are in Table 2). This suggested that non-disjoint chromosomes are preferentially pulled towards the old centrosomes, possibly due to a higher stability of the kinetochore–microtubules emanating from the old centrosomes, which in a tug-of-war would favour a destabilization and release of the kinetochore–microtubules bound to the young pole. To test this hypothesis, we treated cells with Nnf1 and Cenexin siRNAs, which had abolished the bias in chromosome alignment and the asymmetry in the percentage of end-on attached kinetochores. In both cases, the bias in chromosome mis-segregation was abolished (Figure 4C; Video 2 and 3); in contrast when we depleted MCAK, which did not abolish the bias in chromosome alignment, chromosome mis-segregation was still biased (Figure 4C). We conclude that the difference in the stability of kinetochore–microtubules bound to the old or the young centrosome persists in anaphase, and that this difference causes non-disjoint chromosomes to co-segregate with old centrosomes.

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Our results demonstrate that even in symmetrically dividing cells the two half-spindles behave in an asymmetric manner, and that centrosome age imposes a functional asymmetry on all mitotic spindles (see model Figure 4D). We find that this asymmetry reflects a differential stability of kinetochore–microtubules that depends on the presence of cenexin at old centrosomes, indicating that its presence influences the relative stability of kinetochore–microtubules. Previous studies demonstrated that knock-out of cenexin does not impair mitotic progression; it contributes, however, to the stability of the centrosome-bound microtubules during interphase, consistent with our findings that cenexin affects mitotic microtubules (Ishikawa et al., 2005; Tateishi et al., 2013). Cenexin is known since a long time as a marker for old centrioles (Lange and Gull, 1995), yet the molecular mechanisms by which it affects microtubules are unclear. It is required for the formation of distal and sub-distal appendages on the oldest centriole, two structures that are essential for the formation of basal bodies during ciliogenesis (Ishikawa et al., 2005). These structures consist of more then ten different centrosomal proteins, including CEP164, CEP123, CEP83, SCLT1 and FBF1 at the distal appendages and ninein, centriolin, ε-tubulin, trichoplein and CEP170 at sub-distal appendages (Mogensen et al., 2000; Chang et al., 2003; Gromley et al., 2003; Guarguaglini et al., 2005; Graser et al., 2007; Ibi et al., 2011; Sillibourne et al., 2013; Tanos et al., 2013; Tateishi et al., 2013). Moreover Plk1 has been shown to bind Odf2 at centrosomes (Soung et al., 2009). Future work will thus have to evaluate whether the ability to stabilize microtubules is a direct function of cenexin, or a more general function of centriolar appendages. We speculate that cenexin or some of its associated centrosomal proteins might control microtubule stability via three potential mechanisms: first, they could directly interact with microtubule plus-ends, as has been seen for γ-tubulin (Bouissou et al., 2009); second, they could affect microtubule plus-end dynamics by controlling the dynamics of the minus-end, a type of regulation that has been seen in the context of poleward microtubule flux (Maddox et al., 2003; Ganem et al., 2005; Matos et al., 2009); third they could act via centrosomal protein kinases, as it has been recently shown as a proof-of-principle that centrosomal-bound Aurora-A has the ability to regulate kinetochore–microtubule attachments (Chmátal et al., 2015; Ye et al., 2015).

The asymmetry in kinetochore–microtubule stability persists throughout mitosis and directs the fate of non-disjoint chromosomes, which co-segregate mostly with the old centrosome. At present it is unclear whether this asymmetry serves a direct purpose during mitosis, or if it a consequence of a centrosome asymmetry that is required for a non-mitotic function, but which cells have to deal with during each cell division. Possible non-mitotic purposes of this asymmetry include the necessity to only have one centriole capable of generating the basal body of a cilium, or the requirement to only have one centriole capable of anchoring interphase microtubules (Piel et al., 2000; Nigg and Raff, 2009). A possible mitotic function for an asymmetric behaviour of centrosomes is that it might protect stem cells that inherit the old centrosome, from losing non-disjoint chromosomes. This would provide a selective advantage, as haplo-insufficiency is much more frequent than triplo-lethality at the level of single genes in animal cells (Lindsley et al., 1972; Torres et al., 2007). We speculate that the asymmetric distribution of non-disjoint chromosomes might, however, also favour the rapid acquisition of new traits by co-occurrence of chromosome gains in cancer-stem cells. Even though gain/loss of non-disjoint chromosomes is only one of the causes of chromosomal instability in cancer cells, chromosome gain of non-disjoint chromosomes would not be random, but a favoured behaviour in cancer stem cells. Such a potential bias should thus be considered when modelling chromosomal instability in aneuploid cancer cell populations. Consistent with this hypothesis we note that the analysis of large human cancer samples reveals that whole chromosome gains (or losses) co-occur at much higher frequencies than combined chromosome gains and losses (Ozery-Flato et al., 2011). This phenomenon was so far thought to be the result of an evolutionary pressure; we propose that an asymmetric chromosome mis-segregation in cancer stem cells might provide a direct mechanistic explanation for this behaviour. Moreover, it could suggest a more general asymmetry in chromosomal instability, pointing to the need to determine whether other forms of chromosome mis-segregation, such as gain/loss of merotelic chromosomes, depend on centrosome age or not.

1. 1. Aguilera A
   2. García-Muse T

   (2013) Causes of genome instability

   Annual Review of Genetics 47:1–32.

   https://doi.org/10.1146/annurev-genet-111212-133232

   • Google Scholar
2. 1. Amaro AC
   2. Samora CP
   3. Holtackers R
   4. Wang E
   5. Kingston IJ
   6. Alonso M
   7. Lampson M
   8. McAinsh AD
   9. Meraldi P

   (2010) Molecular control of kinetochore–microtubule dynamics and chromosome oscillations

   Nature Cell Biology 12:319–329.

   https://doi.org/10.1038/ncb2033

   • Google Scholar
3. 1. Bakhoum SF
   2. Kabeche L
   3. Murnane JP
   4. Zaki BI
   5. Compton DA

   (2014) DNA-damage response during mitosis induces whole-chromosome missegregation

   Cancer Discovery 4:1281–1289.

   https://doi.org/10.1158/2159-8290

   • Google Scholar
4. 1. Bakhoum SF
   2. Thompson SL
   3. Manning AL
   4. Compton DA

   (2009) Genome stability is ensured by temporal control of kinetochore–microtubule dynamics

   Nature Cell Biology 11:27–35.

   https://doi.org/10.1038/ncb1809

   • Google Scholar
5. 1. Barisic M
   2. Aguiar P
   3. Geley S
   4. Maiato H

   (2014) Kinetochore motors drive congression of peripheral polar chromosomes by overcoming random arm-ejection forces

   Nature Cell Biology 16:1249–1256.

   https://doi.org/10.1038/ncb3060

   • Google Scholar
6. 1. Barisic M
   2. Silva e Sousa R
   3. Tripathy SK
   4. Magiera MM
   5. Zaytsev AV
   6. Pereira AL
   7. Janke C
   8. Grishchuk EL
   9. Maiato H

   (2015) Mitosis. Microtubule detyrosination guides chromosomes during mitosis

   Science 348:799–803.

   https://doi.org/10.1126/science.aaa5175

   • Google Scholar
7. 1. Bouissou A
   2. Vérollet C
   3. Sousa A
   4. Sampaio P
   5. Wright M
   6. Sunkel CE
   7. Merdes A
   8. Raynaud-Messina B

   (2009) {gamma}-Tubulin ring complexes regulate microtubule plus end dynamics

   The Journal of Cell Biology 187:327–334.

   https://doi.org/10.1083/jcb.200905060

   • Google Scholar
8. 1. Chang P
   2. Giddings TH Jr
   3. Winey M
   4. Stearns T

   (2003) Epsilon-tubulin is required for centriole duplication and microtubule organization

   Nature Cell Biology 5:71–76.

   https://doi.org/10.1038/ncb900

   • Google Scholar
9. 1. Chmátal L
   2. Yang K
   3. Schultz RM
   4. Lampson MA

   (2015) Spatial regulation of kinetochore microtubule attachments by destabilization at spindle poles in meiosis I

   Current Biology 25:1835–1841.

   https://doi.org/10.1016/j.cub.2015.05.013

   • Google Scholar
10. 1. Conduit PT
    2. Raff JW

    (2010) Cnn dynamics drive centrosome size asymmetry to ensure daughter centriole retention in Drosophila neuroblasts

    Current Biology 20:2187–2192.

    https://doi.org/10.1016/j.cub.2010.11.055

    • Google Scholar
11. 1. Ganem NJ
    2. Compton DA

    (2004) The KinI kinesin Kif2a is required for bipolar spindle assembly through a functional relationship with MCAK

    The Journal of Cell Biology 166:473–478.

    https://doi.org/10.1083/jcb.200404012

    • Google Scholar
12. 1. Ganem NJ
    2. Upton K
    3. Compton DA

    (2005) Efficient mitosis in human cells lacking poleward microtubule flux

    Current Biology 15:1827–1832.

    https://doi.org/10.1016/j.cub.2005.08.065

    • Google Scholar
13. 1. Graser S
    2. Stierhof YD
    3. Lavoie SB
    4. Gassner OS
    5. Lamla S
    6. Le Clech M
    7. Nigg EA

    (2007) Cep164, a novel centriole appendage protein required for primary cilium formation

    The Journal of Cell Biology 179:321–330.

    https://doi.org/10.1083/jcb.200707181

    • Google Scholar
14. 1. Gromley A
    2. Jurczyk A
    3. Sillibourne J
    4. Halilovic E
    5. Mogensen M
    6. Groisman I
    7. Blomberg M
    8. Doxsey S

    (2003) A novel human protein of the maternal centriole is required for the final stages of cytokinesis and entry into S phase

    The Journal of Cell Biology 161:535–545.

    https://doi.org/10.1083/jcb.200301105

    • Google Scholar
15. 1. Guarguaglini G
    2. Duncan PI
    3. Stierhof YD
    4. Holmström T
    5. Duensing S
    6. Nigg EA

    (2005) The forkhead-associated domain protein Cep170 interacts with Polo-like kinase 1 and serves as a marker for mature centrioles

    Molecular Biology of the Cell 16:1095–1107.

    https://doi.org/10.1091/mbc.E04-10-0939

    • Google Scholar
16. 1. Hauf S
    2. Cole RW
    3. LaTerra S
    4. Zimmer C
    5. Schnapp G
    6. Walter R
    7. Heckel A
    8. van Meel J
    9. Rieder CL
    10. Peters JM

    (2003)

    The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore–microtubule attachment and in maintaining the spindle assembly checkpoint

    The Journal of Cell Biology 161:281–294.

    • Google Scholar
17. 1. Hoyer-Fender S

    (2010) Centriole maturation and transformation to basal body

    Seminars in Cell & Developmental Biology 21:142–147.

    https://doi.org/10.1016/j.semcdb.2009.07.002

    • Google Scholar
18. 1. Ibi M
    2. Zou P
    3. Inoko A
    4. Shiromizu T
    5. Matsuyama M
    6. Hayashi Y
    7. Enomoto M
    8. Mori D
    9. Hirotsune S
    10. Kiyono T
    11. Tsukita S
    12. Goto H
    13. Inagaki M

    (2011) Trichoplein controls microtubule anchoring at the centrosome by binding to Odf2 and ninein

    Journal of Cell Science 124:857–864.

    https://doi.org/10.1242/jcs.075705

    • Google Scholar
19. 1. Ishikawa H
    2. Kubo A
    3. Tsukita S
    4. Tsukita S

    (2005) Odf2-deficient mother centrioles lack distal/subdistal appendages and the ability to generate primary cilia

    Nature Cell Biology 7:517–524.

    https://doi.org/10.1038/ncb1251

    • Google Scholar
20. 1. Januschke J
    2. Reina J
    3. Llamazares S
    4. Bertran T
    5. Rossi F
    6. Roig J
    7. Gonzalez C

    (2013) Centrobin controls mother-daughter centriole asymmetry in Drosophila neuroblasts

    Nature Cell Biology 15:241–248.

    https://doi.org/10.1038/ncb2671

    • Google Scholar
21. 1. Januschke J
    2. Llamazares S
    3. Reina J
    4. Gonzalez C

    (2011) Drosophila neuroblasts retain the daughter centrosome

    Nature Communications 2:243.

    https://doi.org/10.1038/ncomms1245

    • Google Scholar
22. 1. Kapoor TM
    2. Lampson MA
    3. Hergert P
    4. Cameron L
    5. Cimini D
    6. Salmon ED
    7. McEwen BF
    8. Khodjakov A

    (2006) Chromosomes can congress to the metaphase plate before biorientation

    Science 311:388–391.

    https://doi.org/10.1126/science.1122142

    • Google Scholar
23. 1. Khodjakov AL
    2. Rieder CL

    (1999)

    The sudden recruitment of gamma-tubulin to the centrosome at the onset of mitosis and its dynamic exchange throughout the cell cycle, do not require microtubules

    The Journal of Cell Biology 146:585–596.

    • Google Scholar
24. 1. Kline SL
    2. Cheeseman IM
    3. Hori T
    4. Fukagawa T
    5. Desai A

    (2006) The human Mis12 complex is required for kinetochore assembly and proper chromosome segregation

    The Journal of Cell Biology 173:9–17.

    https://doi.org/10.1083/jcb.200509158

    • Google Scholar
25. 1. Knowlton AL
    2. Lan W
    3. Stukenberg PT

    (2006)

    Aurora B is enriched at merotelic attachment sites, where it regulates MCAK

    Current Biology 16:1705–1710.

    • Google Scholar
26. 1. Kops GJPL
    2. Saurin AT
    3. Meraldi P

    (2010) Finding the middle ground: how kinetochores power chromosome congression

    Cellular and Molecular Life Sciences 67:2145–2161.

    https://doi.org/10.1007/s00018-010-0321-y

    • Google Scholar
27. 1. Kuo TC
    2. Chen CT
    3. Baron D
    4. Onder TT
    5. Loewer S
    6. Almeida S
    7. Weismann CM
    8. Xu P
    9. Houghton JM
    10. Gao FB
    11. Daley GQ
    12. Doxsey S

    (2011) Midbody accumulation through evasion of autophagy contributes to cellular reprogramming and tumorigenicity

    Nature Cell Biology 13:1214–1223.

    https://doi.org/10.1038/ncb2332

    • Google Scholar
28. 1. Lange BM
    2. Gull K

    (1995)

    A molecular marker for centriole maturation in the mammalian cell cycle

    The Journal of Cell Biology 130:919–927.

    • Google Scholar
29. 1. Lerit DA
    2. Rusan NM

    (2013) PLP inhibits the activity of interphase centrosomes to ensure their proper segregation in stem cells

    The Journal of Cell Biology 202:1013–1022.

    https://doi.org/10.1083/jcb.201303141

    • Google Scholar
30. 1. Lindsley DL
    2. Sandler L
    3. Baker BS
    4. Carpenter AT
    5. Denell RE
    6. Hall JC
    7. Jacobs PA
    8. Miklos GL
    9. Davis BK
    10. Gethmann RC
    11. Hardy RW
    12. Steven AH
    13. Miller M
    14. Nozawa H
    15. Parry DM
    16. Gould-Somero M
    17. Gould-Somero M

    (1972)

    Segmental aneuploidy and the genetic gross structure of the Drosophila genome

    Genetics 71:157–184.

    • Google Scholar
31. 1. Liu D
    2. Davydenko O
    3. Lampson MA

    (2012) Polo-like kinase-1 regulates kinetochore–microtubule dynamics and spindle checkpoint silencing

    The Journal of Cell Biology 198:491–499.

    https://doi.org/10.1083/jcb.201205090

    • Google Scholar
32. 1. Logarinho E
    2. Maffini S
    3. Barisic M
    4. Marques A
    5. Toso A
    6. Meraldi P
    7. Maiato H

    (2012) CLASPs prevent irreversible multipolarity by ensuring spindle-pole resistance to traction forces during chromosome alignment

    Nature Cell Biology 14:295–303.

    https://doi.org/10.1038/ncb2423

    • Google Scholar
33. 1. Maddox P
    2. Straight A
    3. Coughlin P
    4. Mitchison TJ
    5. Salmon ED

    (2003) Direct observation of microtubule dynamics at kinetochores in Xenopus extract spindles: implications for spindle mechanics

    The Journal of Cell Biology 162:377–382.

    https://doi.org/10.1083/jcb.200301088

    • Google Scholar
34. 1. Matos I
    2. Pereira AJ
    3. Lince-Faria M
    4. Cameron LA
    5. Salmon ED
    6. Maiato H

    (2009) Synchronizing chromosome segregation by flux-dependent force equalization at kinetochores

    The Journal of Cell Biology 186:11–26.

    https://doi.org/10.1083/jcb.200904153

    • Google Scholar
35. 1. Mayer TU
    2. Kapoor TM
    3. Haggarty SJ
    4. King RW
    5. Schreiber SL
    6. Mitchison TJ

    (1999)

    Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen

    Science 286:971–974.

    • Google Scholar
36. 1. McAinsh AD
    2. Meraldi P
    3. Draviam VM
    4. Toso A
    5. Sorger PK

    (2006) The human kinetochore proteins Nnf1R and Mcm21R are required for accurate chromosome segregation

    The EMBO Journal 25:4033–4049.

    https://doi.org/10.1038/sj.emboj.7601293

    • Google Scholar
37. 1. McHedlishvili N
    2. Wieser S
    3. Holtackers R
    4. Mouysset J
    5. Belwal M
    6. Amaro AC
    7. Meraldi P

    (2012) Kinetochores accelerate centrosome separation to ensure faithful chromosome segregation

    Journal of Cell Science 125:906–918.

    https://doi.org/10.1242/jcs.091967

    • Google Scholar
38. 1. Meraldi P
    2. Draviam VM
    3. Sorger PK

    (2004) Timing and checkpoints in the regulation of mitotic progression

    Developmental Cell 7:45–60.

    https://doi.org/10.1016/j.devcel.2004.06.006

    • Google Scholar
39. 1. Mogensen MM
    2. Malik A
    3. Piel M
    4. Bouckson-Castaing V
    5. Bornens M

    (2000)

    Microtubule minus-end anchorage at centrosomal and non-centrosomal sites: the role of ninein

    Journal of Cell Science 113:3013–3023.

    • Google Scholar
40. 1. Nigg EA
    2. Raff JW

    (2009) Centrioles, centrosomes, and cilia in health and disease

    Cell 139:663–678.

    https://doi.org/10.1016/j.cell.2009.10.036

    • Google Scholar
41. 1. Nigg EA
    2. Stearns T

    (2011) The centrosome cycle: centriole biogenesis, duplication and inherent asymmetries

    Nature Cell Biology 13:1154–1160.

    https://doi.org/10.1038/ncb2345

    • Google Scholar
42. 1. Ozery-Flato M
    2. Linhart C
    3. Trakhtenbrot L
    4. Izraeli S
    5. Shamir R

    (2011) Large-scale analysis of chromosomal aberrations in cancer karyotypes reveals two distinct paths to aneuploidy

    Genome Biology 12:R61.

    https://doi.org/10.1186/gb-2011-12-6-r61

    • Google Scholar
43. 1. Paridaen JTML
    2. Wilsch-Bräuninger M
    3. Huttner WB

    (2013) Asymmetric inheritance of centrosome-associated primary cilium membrane directs ciliogenesis after cell division

    Cell 155:333–344.

    https://doi.org/10.1016/j.cell.2013.08.060

    • Google Scholar
44. 1. Piel M
    2. Meyer P
    3. Khodjakov A
    4. Rieder CL
    5. Bornens M

    (2000)

    The respective contributions of the mother and daughter centrioles to centrosome activity and behavior in vertebrate cells

    The Journal of Cell Biology 149:317–330.

    • Google Scholar
45. 1. Rieder CL
    2. Borisy GG

    (1982)

    The Centrosome Cycle in PtK2 Cells: asymmetric distribution and structural changes in the pericentriolar material

    Biology of the cell/under the auspices of the European Cell Biology Organization 44:117–132.

    • Google Scholar
46. 1. Sillibourne JE
    2. Hurbain I
    3. Grand-Perret T
    4. Goud B
    5. Tran P
    6. Bornens M

    (2013) Primary ciliogenesis requires the distal appendage component Cep123

    Biology Open 2:535–545.

    https://doi.org/10.1242/bio.20134457

    • Google Scholar
47. 1. Soung NK
    2. Park JE
    3. Yu LR
    4. Lee KH
    5. Lee JM
    6. Bang JK
    7. Veenstra TD
    8. Rhee K
    9. Lee KS

    (2009) Plk1-dependent and -independent roles of an ODF2 splice variant, hCenexin1, at the centrosome of somatic cells

    Developmental Cell 16:539–550.

    https://doi.org/10.1016/j.devcel.2009.02.004

    • Google Scholar
48. 1. Tanos BE
    2. Yang HJ
    3. Soni R
    4. Wang WJ
    5. Macaluso FP
    6. Asara JM
    7. Tsou MF

    (2013) Centriole distal appendages promote membrane docking, leading to cilia initiation

    Genes & Development 27:163–168.

    https://doi.org/10.1101/gad.207043.112

    • Google Scholar
49. 1. Tateishi K
    2. Yamazaki Y
    3. Nishida T
    4. Watanabe S
    5. Kunimoto K
    6. Ishikawa H
    7. Tsukita S

    (2013) Two appendages homologous between basal bodies and centrioles are formed using distinct Odf2 domains

    The Journal of Cell Biology 203:417–425.

    https://doi.org/10.1083/jcb.201303071

    • Google Scholar
50. 1. Torres EM
    2. Sokolsky T
    3. Tucker CM
    4. Chan LY
    5. Boselli M
    6. Dunham MJ
    7. Amon A

    (2007) Effects of aneuploidy on cellular physiology and cell division in haploid yeast

    Science 317:916–924.

    https://doi.org/10.1126/science.1142210

    • Google Scholar
51. 1. Vasquez RJ
    2. Howell B
    3. Yvon AM
    4. Wadsworth P
    5. Cassimeris L

    (1997)

    Nanomolar concentrations of nocodazole alter microtubule dynamic instability in vivo and in vitro

    Molecular Biology of the Cell 8:973–985.

    • Google Scholar
52. 1. Wang X
    2. Tsai JW
    3. Imai JH
    4. Lian WN
    5. Vallee RB
    6. Shi SH

    (2009) Asymmetric centrosome inheritance maintains neural progenitors in the neocortex

    Nature 461:947–955.

    https://doi.org/10.1038/nature08435

    • Google Scholar
53. 1. Webster DR
    2. Borisy GG

    (1989)

    Microtubules are acetylated in domains that turn over slowly

    Journal of Cell Science 92:57–65.

    • Google Scholar
54. 1. Wood KW
    2. Sakowicz R
    3. Goldstein LS
    4. Cleveland DW

    (1997)

    CENP-E is a plus end-directed kinetochore motor required for metaphase chromosome alignment

    Cell 91:357–366.

    • Google Scholar
55. 1. Yamashita YM
    2. Mahowald AP
    3. Perlin JR
    4. Fuller MT

    (2007) Asymmetric inheritance of mother versus daughter centrosome in stem cell division

    Science 315:518–521.

    https://doi.org/10.1126/science.1134910

    • Google Scholar
56. 1. Ye AA
    2. Deretic J
    3. Hoel CM
    4. Hinman AW
    5. Cimini D
    6. Welburn JP
    7. Maresca TJ

    (2015) Aurora a kinase contributes to a pole-based error correction pathway

    Current Biology 25:1842–1851.

    https://doi.org/10.1016/j.cub.2015.06.021

    • Google Scholar

Author details

1. Ivana Gasic

   1. Department of Cellular Physiology and Metabolism, University of Geneva, Geneva, Switzerland
   2. Institute of Biochemistry, Eidgenössische Technische Hochschule Zürich, Zürich, Switzerland

   Contribution

   IG, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

2. Purnima Nerurkar

   Institute of Biochemistry, Eidgenössische Technische Hochschule Zürich, Zürich, Switzerland

   Contribution

   PN, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

3. Patrick Meraldi

   Department of Cellular Physiology and Metabolism, University of Geneva, Geneva, Switzerland

   Contribution

   PM, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   Patrick.meraldi@unige.ch

   Competing interests

   The authors declare that no competing interests exist.

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