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A Stochastic Model of Kinetochore–Microtubule Attachment Accurately A stochastic model of kinetochore–microtubule attachment accurately describes fission yeast chromosome segregation Guillaume Gay, Thibault Courthéoux, Céline Reyes, Sylvie Tournier, Yannick Gachet To cite this version: Guillaume Gay, Thibault Courthéoux, Céline Reyes, Sylvie Tournier, Yannick Gachet. A stochas- tic model of kinetochore–microtubule attachment accurately describes fission yeast chromosome segregation. Journal of Cell Biology, Rockefeller University Press, 2012, 196 (6), pp.757-774. 10.1083/jcb.201107124. hal-02380748 HAL Id: hal-02380748 https://hal.archives-ouvertes.fr/hal-02380748 Submitted on 26 Nov 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Published March 12, 2012 JCB: Article A stochastic model of kinetochore–microtubule attachment accurately describes fission yeast chromosome segregation Guillaume Gay,1,2 Thibault Courtheoux,1,2 Céline Reyes,1,2 Sylvie Tournier,1,2 and Yannick Gachet1,2 1Laboratoire de biologie cellulaire et moléculaire du contrôle de la proliferation, Université de Toulouse, F-31062 Toulouse, France 2Unité Mixte de Recherche 5088, Centre National de la Recherche Scientifique, F-31062 Toulouse, France n fission yeast, erroneous attachments of spindle micro­ segregation seen in fission yeast. Prevention of attachment tubules to kinetochores are frequent in early mitosis. defects requires both appropriate kinetochore orientation Most are corrected before anaphase onset by a mech­ and an Aurora B–like activity. The model also reproduces I Downloaded from anism involving the protein kinase Aurora B, which desta­ abnormal chromosome segregation behavior (caused by, bilizes kinetochore microtubules (ktMTs) in the absence of for example, inhibition of Aurora B). It predicts that, in tension between sister chromatids. In this paper, we de­ metaphase, merotelic attachment is prevented by a kinet­ scribe a minimal mathematical model of fission yeast chro­ ochore orientation effect and corrected by an Aurora B–like mosome segregation based on the stochastic attachment activity, whereas in anaphase, it is corrected through unbal­ and detachment of ktMTs. The model accurately repro­ anced forces applied to the kinetochore. These unbalanced duces the timing of correct chromosome biorientation and forces are sufficient to prevent aneuploidy. jcb.rupress.org Introduction on August 21, 2012 The fidelity of chromosome attachment to the mitotic spindle is equidistantly between the two centrosomes because of forces crucial to preventing the formation of aneuploid cells. To this generated by kinetochore-bound mitotic motors (kinesins and end, kinetochores, protein structures that assemble at the cen- dynein; Kops et al., 2010). Once the chromosomes are correctly tromeres of each pair of sister chromatids, must attach to micro- bioriented, sister chromatids separate and move simultaneously tubules from opposite spindle poles (chromosome biorientation) toward the poles (Uhlmann et al., 1999; Oliveira et al., 2010). The before the onset of anaphase. Precisely how the spindle captures correct back to back arrangement of sister kinetochores (kineto- and faithfully biorients all chromosomes within the short time chore geometry) is crucial to prevent chromosome loss through THE JOURNAL OF CELL BIOLOGY between prophase and anaphase onset remains a fundamental defects, such as merotelic attachment, in which one kinetochore question in biology. The bipolar mitotic spindle assembles during is attached to both poles (Gregan et al., 2007; Courtheoux et al., prometaphase by a “search and capture” process in which dy- 2009; Sakuno et al., 2009; Gregan et al., 2011). Sister chromatid namically unstable microtubules make associations with kineto- cohesion may thus define correct kinetochore geometry. chores (Kirschner and Mitchison, 1986). The search and capture In the symmetrically dividing fission yeast Schizosaccha- of kinetochores by microtubules is a common feature of mitosis romyces pombe, segregation of the three mitotic chromosomes in eukaryotes, which was initially visualized in newt lung cells occurs within the nuclear envelope (so-called closed mitosis). The (Hayden et al., 1990; Rieder and Alexander, 1990) and subse- six kinetochores each contain attachment sites for up to four micro- quently characterized in budding and fission yeasts (Tanaka tubules (Ding et al., 1993) emanating from the centrosome, also et al., 2005, 2007; Franco et al., 2007; Gachet et al., 2008). After called the spindle pole body (SPB). The two SPBs also nucleate capture, chromosomes align at the metaphase plate, which forms microtubules that interdigitate at the spindle center. Mitosis in S. pombe consists of three phases (Nabeshima et al., 1998; G. Gay and T. Courtheoux contributed equally to this paper. Correspondence to Sylvie Tournier: [email protected]; or Yannick Gachet: © 2012 Gay et al. This article is distributed under the terms of an Attribution– [email protected] Noncommercial–Share Alike–No Mirror Sites license for the first six months after the pub- lication date (see http://www.rupress.org/terms). After six months it is available under a Abbreviations used in this paper: ktMT, kinetochore microtubule; SAC, spindle Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, assembly checkpoint; SPB, spindle pole body. as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). Supplemental Material can be found at: http://jcb.rupress.org/content/suppl/2012/03/07/jcb.201107124.DC1.html The Rockefeller University Press $30.00 J. Cell Biol. Vol. 196 No. 6 757–774 www.jcb.org/cgi/doi/10.1083/jcb.201107124 JCB 757 Published March 12, 2012 Downloaded from jcb.rupress.org on August 21, 2012 Figure 1. Schematic representation of the metaphase spindle. (A) In vivo. (left) The two SPBs are linked by overlapping interdigitated microtubules (MT). The chromosome (gray) is linked to the SPBs by its centromere regions. The four microtubule attachment sites located on each kinetochore (Kt) are connected to the SPBs by ktMTs. The two sister chromatids are held together by the cohesin complex. (right) Schematic depiction illustrating the in vivo structure of 758 JCB • VOLUME 196 • NUMBER 6 • 2012 Published March 12, 2012 Tatebe et al., 2001). During phase 1, a short (<2.0 µm) spindle anaphase, we have designed a biophysical model of mitosis based is formed. In phase 2 (prometaphase/metaphase/anaphase A), on data obtained by video microscopy of living fission yeast cells. the spindle maintains roughly the same length, and the kineto- Although mathematical and computational models of mitosis have chores make frequent, rapid oscillations between the poles. been developed over the past few years, none have combined a At the end of phase 2, the kinetochores congress to the spindle mechanical description of chromosome segregation with the cor- midzone; the sister chromatids then separate and move toward rection of attachment defects (Brust-Mascher et al., 2004; Gardner the SPBs during anaphase A (Tournier et al., 2004). In phase 3 et al., 2005; Civelekoglu-Scholey et al., 2006; Courtheoux et al., (anaphase B), the spindle elongates along the longitudinal axis 2009; Paul et al., 2009). Our new model faithfully reproduces of the cell. fission yeast chromosome oscillations and segregation from pro- The spindle assembly checkpoint (SAC) controls the tim- phase to anaphase B, and it predicts the attachment state of all ing of anaphase onset to prevent chromosome loss as the result three chromosomes with time. It also predicts that the duration of incorrect attachments (Rieder et al., 1995; Rudner and Murray, of phase 1 and 2 (prometaphase/metaphase/anaphase A) is long 1996; Cleveland et al., 2003). Components of the SAC were first enough to allow proper biorientation to occur through a stochastic identified in the budding yeastSaccharomyces cerevisiae (Hoyt succession of attachment and detachment events biased toward et al., 1991; Li and Murray, 1991), but structural and functional biorientation. Finally, the model reproduces abnormal behavior homologues of mitotic checkpoint proteins have since been iden- of chromosome segregation after inhibition of Aurora B and pre- tified in all other eukaryotes examined, including fission yeast dicts that merotelic attachments can also be corrected after ana- (He et al., 1997; Bernard et al., 1998; Millband and Hardwick, phase onset by an imbalance of forces exerted by microtubules 2002). In response to microtubule-disrupting agents, checkpoint on the merotelic kinetochore. We conclude that two independent Downloaded from proteins translocate to unattached kinetochores and delay the mechanisms, kinetochore orientation and Aurora-like activity, onset of anaphase. Aurora B kinases are also essential for accurate are required to prevent the appearance of merotelic attachment chromosome segregation (Lampson and Cheeseman, 2011). This and the cut phenotype after anaphase onset. kinase was first identified in S. cerevisiae (as Ipl1) in a screen for mutants that display an increase in ploidy
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