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• W2029576146 abstract "Sets of overlapping microtubules support the segregation of chromosomes by linking the poles of mitotic spindles. Recent work examines the effect of putting these linkages under pressure by the activation of dicentric chromosomes and sheds new light on the structural role of several well-known spindle midzone proteins. Sets of overlapping microtubules support the segregation of chromosomes by linking the poles of mitotic spindles. Recent work examines the effect of putting these linkages under pressure by the activation of dicentric chromosomes and sheds new light on the structural role of several well-known spindle midzone proteins. The segregation of chromosomes during cell division is coordinated by the intensely studied microtubule-based mitotic spindle. This apparatus lines up pairs of duplicated chromosomes between two spindle poles during metaphase (Figure 1). But, after disruption of their connections at the start of anaphase A, sister chromosomes go their separate ways and hitch a ride on the tips of depolymerizing microtubules towards the poles. The cells pinch themselves between the poles such that the poles and their attached chromosomes are separated for good into two new cells. The microtubules that constitute the spindle are named after their linkages: microtubules that connect spindle poles and chromosomes are dubbed kinetochore microtubules (kMTs), after the specialized attachment sites for microtubules at chromosomes. Interpolar microtubules (ipMTs) also emanate from the poles but are bundled together with partner microtubules coming from the sister pole. These bundled ipMTs act as central axes within the spindle that provides structural support and ensures that the poles stay separated. In fact, during anaphase B, these antiparallel overlapping microtubules slide relative to each other, thereby further increasing the distance between the poles. A recent study in the budding yeast Saccharomyces cerevisiae now suggests roles for the microtubule-based motor Kar3 (Kinesin-14) and the microtubule plus-end-tracking protein Bim1 (EB1) in organizing microtubule overlap [1Gardner M.K. Haase J. Mythreye K. Molk J.N. Anderson M. Joglekar A.P. O'Toole E.T. Winey M. Salmon E.D. Odde D.J. et al.The microtubule-based motor Kar3 and plus end binding protein Bim1 provide structural support for the anaphase spindle.J. Cell Biol. 2008; 180: 91-100Crossref PubMed Scopus (54) Google Scholar]. The mitotic spindle of budding yeast contains 32 kMTs — two for each pair of chromosomes — and approximately eight ipMTs. The ipMTs interdigitate in a spatially restricted region that, most strikingly throughout anaphase B, remains precisely centered between the spindle poles and is therefore named the midzone. The midzone has a key role in establishing spindle bipolarity because it selectively links antiparallel microtubules. The ipMTs that make up the midzone are dynamic, cycling between periods of growth and shrinkage. During anaphase B, ipMTs go through a period of net growth, which facilitates spindle elongation through relative sliding of extending microtubules. Throughout anaphase, shrinking ipMTs must be prevented from shortening all the way back to the poles, as this would cause a mechanical destabilization of the midzone (Figure 1). So, how are microtubule plus ends spatially restricted to the midzone and how is sliding regulated? A variety of ‘midzone proteins’ localizes to the midzone, including kinesin motors, microtubule-associated proteins (MAPs), kinases and phosphatases. Their intriguing modes of interaction and effects on events at the midzone are now slowly being revealed. In the recent work, Gardner et al. [1Gardner M.K. Haase J. Mythreye K. Molk J.N. Anderson M. Joglekar A.P. O'Toole E.T. Winey M. Salmon E.D. Odde D.J. et al.The microtubule-based motor Kar3 and plus end binding protein Bim1 provide structural support for the anaphase spindle.J. Cell Biol. 2008; 180: 91-100Crossref PubMed Scopus (54) Google Scholar] designed an assay that probes the stability of the midzone using conditionally functional dicentric chromosomes, i.e. chromosomes with two centromeres, one of which can be switched on and off. Once activated, these chromosomes form a second microtubule attachment site away from the primary kinetochore. Consequently, there is a 50% chance that individual dicentric chromosomes become connected to both spindle poles. The equal, but oppositely directed, pulling forces that are then exerted on the primary and secondary kinetochore satisfy the spindle checkpoint, but, upon entry into anaphase, the chromosome is left in limbo over which way to move. The central axis of ipMTs is pressurized by the pulling forces at the kinetochores and may collapse or break if the midzone is structurally challenged. A broken spindle inhibits spindle elongation in anaphase B and intact chromosomes will missegregate, ultimately leading to cell death (Figure 1C). A drastic decrease in cell viability upon dicentric chromosome activation was indeed found following the loss of the midzone-associated proteins Bim1, Kar3, Cik1 (a Kar3-binding protein), Ase1 (PRC1; a microtubule-bundling protein), Bik1 (Clip170), and Slk19 (a chromosomal passenger protein). A structurally intact midzone, on the other hand, will resist pulling forces exerted at the kinetochores during anaphase, and the dicentric chromosomes will be stretched: ultimately this may induce chromosomal breakage (Figure 1B). Indeed, wild-type yeast cells that had undergone cell division after the activation of dicentric chromosomes contained rearranged chromosomes — a silent witness of the destructive forces experienced during anaphase. These studies indicate that chromosomes were broken but repaired by recombination. The frequency of these rearrangements was decreased in bim1Δ, ase1Δ and kar3Δ cells, suggesting that the midzone in these cells is weakened and unable to withstand the force required for chromosome stretching/breakage. Midzone mutants pay for their resistance to chromosome breakage by an increase in chromosome missegregation, however. The involvement of the kinesin Kar3 in midzone stability is especially surprising since earlier work reported only a low degree of localization of Kar3 to the anaphase midzone [2Tytell J.D. Sorger P.K. Analysis of kinesin motor function at budding yeast kinetochores.J. Cell Biol. 2006; 172: 861-874Crossref PubMed Scopus (89) Google Scholar]. What are the functions of Ase1, Kar3 and Bim1 in organizing a spatially restricted stable midzone? Together with mammalian PRC1, Ase1 belongs to a conserved family of microtubule-bundling proteins [3Mollinari C. Kleman J.P. Jiang W. Schoehn G. Hunter T. Margolis R.L. PRC1 is a microtubule binding and bundling protein essential to maintain the mitotic spindle midzone.J. Cell Biol. 2002; 157: 1175-1186Crossref PubMed Scopus (317) Google Scholar, 4Schuyler S.C. Liu J.Y. Pellman D. The molecular function of Ase1p: evidence for a MAP-dependent midzone-specific spindle matrix.J. Cell Biol. 2003; 160: 517-528Crossref PubMed Scopus (162) Google Scholar]. The fission yeast (Schizosaccharomyces pombe) homologue of Ase1 was demonstrated to bind selectively to antiparallel microtubules [5Janson M.E. Loughlin R. Loïodice I. Fu C. Brunner D. Nédélec F.J. Tran P.T. Cross-linkers and motors organize dynamic microtubules to form stable bipolar arrays in fission yeast.Cell. 2007; 128: 357-368Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar]. Ase1 may therefore bundle antiparallel microtubules between two spindle poles, thus initiating the formation of the midzone. Spindles of ase1Δ cells are not straight as in wild-type cells, but often appear broken or kinked because of insufficient bundling [4Schuyler S.C. Liu J.Y. Pellman D. The molecular function of Ase1p: evidence for a MAP-dependent midzone-specific spindle matrix.J. Cell Biol. 2003; 160: 517-528Crossref PubMed Scopus (162) Google Scholar, 6Loiodice I. Staub J. Setty T.G. Nguyen N.P.T. Paoletti A. Tran P.T. Ase1p organizes antiparallel microtubule arrays during interphase and mitosis in fission yeast.Mol. Biol. Cell. 2005; 16: 1756-1768Crossref PubMed Scopus (137) Google Scholar]. Bim1, the yeast homologue of the microtubule-growth-promoting factor EB1 [7Tirnauer J.S. O'Toole E.O. Berrueta L. Bierer B.E. Pellman D. Yeast Bim1p promotes the G1-specific dynamics of microtubules.J. Cell Biol. 1999; 145: 993-1007Crossref PubMed Scopus (200) Google Scholar], is expected to function at microtubule plus ends. Cells lacking bim1 have shorter zones of antiparallel overlap compared with wild-type cells, hinting that an overall destabilization of microtubules decreases the length and stability of the midzone [1Gardner M.K. Haase J. Mythreye K. Molk J.N. Anderson M. Joglekar A.P. O'Toole E.T. Winey M. Salmon E.D. Odde D.J. et al.The microtubule-based motor Kar3 and plus end binding protein Bim1 provide structural support for the anaphase spindle.J. Cell Biol. 2008; 180: 91-100Crossref PubMed Scopus (54) Google Scholar]. In agreement with this idea, loss of the microtubule-destabilizing protein Kip3 in the bim1Δ cells partially restored spindle stability. Kar3 is a minus-end-directed kinesin that forms a heterodimer with the non-motor protein Cik1 and localizes to microtubule plus ends where it can form a force-generating bridge with overlapping microtubules [1Gardner M.K. Haase J. Mythreye K. Molk J.N. Anderson M. Joglekar A.P. O'Toole E.T. Winey M. Salmon E.D. Odde D.J. et al.The microtubule-based motor Kar3 and plus end binding protein Bim1 provide structural support for the anaphase spindle.J. Cell Biol. 2008; 180: 91-100Crossref PubMed Scopus (54) Google Scholar, 8Allingham J.S. Sproul L.R. Rayment I. Gilbert S.P. Vik1 modulates microtubule-Kar3 interactions through a motor domain that lacks an active site.Cell. 2007; 128: 1161-1172Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar]. Gardner et al. [1Gardner M.K. Haase J. Mythreye K. Molk J.N. Anderson M. Joglekar A.P. O'Toole E.T. Winey M. Salmon E.D. Odde D.J. et al.The microtubule-based motor Kar3 and plus end binding protein Bim1 provide structural support for the anaphase spindle.J. Cell Biol. 2008; 180: 91-100Crossref PubMed Scopus (54) Google Scholar] propose that these bridges contribute significantly to bundling on the basis of their observation that, in kar3Δ cells, ipMTs often splay outwards, away from the normally straight spindle. As a consequence, kar3Δ cells have a decreased amount of microtubule overlap. The authors propose that this could provide less space for plus-end-directed kinesin-5 motors to bind, explaining why the deletion of a minus-end-directed motor counterintuitively leads to anaphase B spindles (Figure 1C). Although speculative, this proposed mechanism warns us that midzone proteins rely on each other's function in mechanistically unexpected ways. A molecular explanation for the stabilization of microtubules in the midzone of S. pombe is given by Bratman et al. [9Bratman S.V. Chang F. Stabilization of overlapping microtubules by fission yeast CLASP.Dev. Cell. 2007; 13: 812-827Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar]. In a recent paper they demonstrate that Cls1p, a member of the CLASP microtubule-associated protein family, is a direct binding partner of Ase1p. This interaction targets Cls1p to the midzone where it switches/rescues incoming depolymerizing microtubules back to a growth state. In effect, a gradient in rescue frequency is generated in the spindle. Without Cls1p, a centered midzone fails to form and spindles easily break. Interestingly, the localization of Bim1 in S. cerevisiae suggests that its microtubule-stabilizing activity may also be confined to the midzone in a similar way as the restriction of Cls1p activity in S. pombe [1Gardner M.K. Haase J. Mythreye K. Molk J.N. Anderson M. Joglekar A.P. O'Toole E.T. Winey M. Salmon E.D. Odde D.J. et al.The microtubule-based motor Kar3 and plus end binding protein Bim1 provide structural support for the anaphase spindle.J. Cell Biol. 2008; 180: 91-100Crossref PubMed Scopus (54) Google Scholar]. At first sight, the Ase1p–Cls1p interaction would stabilize all antiparallel microtubules. However, since in the straight yeast spindle each microtubule can easily find an antiparallel partner, this would implicate that the rescue frequency would be high throughout the complete spindle. Microtubules would continuously grow, generating an overly long midzone. So somehow, the midzonal proteins need to be spatially confined. One proposal is that the initial confinement occurs on short anaphase A spindles [10Khmelinskii A. Lawrence C. Roostalu J. Schiebel E. Cdc14-regulated midzone assembly controls anaphase B.J. Cell Biol. 2007; 177: 981-993Crossref PubMed Scopus (114) Google Scholar]. The proteins would then remain confined to this length once the spindle elongates. The remarkably slow turnover of Ase1p in yeast spindles may provide the basis of such a mechanism [6Loiodice I. Staub J. Setty T.G. Nguyen N.P.T. Paoletti A. Tran P.T. Ase1p organizes antiparallel microtubule arrays during interphase and mitosis in fission yeast.Mol. Biol. Cell. 2005; 16: 1756-1768Crossref PubMed Scopus (137) Google Scholar]. Interestingly, the work on Clsp1p demonstrates to us how functional modules are recycled in different cell types. In cultured mammalian cells, CLASP proteins help to maintain plus ends of dynamic microtubules at the leading edge through interactions with plus-end-binding proteins [11Mimori-Kiyosue Y. Grigoriev I. Lansbergen G. Sasaki H. Matsui C. Severin F. Galjart N. Grosveld F. Vorobjev I. Tsukita S. et al.CLASP1 and CLASP2 bind to EB1 and regulate microtubule plus-end dynamics at the cell cortex.J. Cell Biol. 2005; 168: 141-153Crossref PubMed Scopus (299) Google Scholar]. The microtubule-stabilizing activity of CLASP proteins is thus targeted to different cellular regions in different cell types through protein–protein interactions that are not necessarily conserved. Additional studies suggest that, more generally, the midzone is a region where a collection of fixed components associate in flexible ways to form a complex that ‘fine-tunes’ spindle assembly according to the specific needs of different cell types. One well-known example is the association between a kinesin motor and a Rho GTPase-activating protein (RhoGAP) in the centralspindlin complex [12Mishima M. Kaitna S. Glotzer M. Central spindle assembly and cytokinesis require a kinesin-like protein/RhoGAP complex with microtubule bundling activity.Dev. Cell. 2002; 2: 41-54Abstract Full Text Full Text PDF PubMed Scopus (397) Google Scholar]. Many other associations seem to involve Ase1/PRC1. For example, previous work has reported an interaction between the mitotic Polo-like kinase 1 and the mammalian Ase1 homologue PRC1 in anaphase that is regulated by cyclin-dependent kinase 1 (Cdk1) [13D'Avino P.P. Archambault V. Przewloka M.R. Zhang W. Lilley K.S. Laue E. Glover D.M. Recruitment of Polo kinase to the spindle midzone during cytokinesis requires the Feo/Klp3A complex.PLoS ONE. 2007; 2: e572Crossref PubMed Scopus (39) Google Scholar, 14Neef R. Gruneberg U. Kopajtich R. Li X.L. Nigg E.A. Sillje H. Barr F.A. Choice of Plk1 docking partners during mitosis and cytokinesis is controlled by the activation state of Cdk1.Nat. Cell Biol. 2007; 9: 436-444Crossref PubMed Scopus (190) Google Scholar]. Also, several kinesins have surprisingly been shown to bind to PRC1 [15Gruneberg U. Neef R. Li X.L. Chan E.H.Y. Chalamalasetty R.B. Nigg E.A. Barr F.A. KIF14 and citron kinase act together to promote efficient cytokinesis.J. Cell Biol. 2006; 172: 363-372Crossref PubMed Scopus (196) Google Scholar]. Recently, Khmelinskii et al. [10Khmelinskii A. Lawrence C. Roostalu J. Schiebel E. Cdc14-regulated midzone assembly controls anaphase B.J. Cell Biol. 2007; 177: 981-993Crossref PubMed Scopus (114) Google Scholar] showed that the chromosomal passenger proteins Esp1 (separase) and Slk19 rely on Ase1 for their targeting to the midzone in yeast. Together, these results suggest that many proteins piggyback directly or indirectly on Ase1/PRC1 towards antiparallel ipMTs. At least some of these interactions, and also the oligomerization state of Ase1/PRC1, seem to be regulated by phosphorylation [14Neef R. Gruneberg U. Kopajtich R. Li X.L. Nigg E.A. Sillje H. Barr F.A. Choice of Plk1 docking partners during mitosis and cytokinesis is controlled by the activation state of Cdk1.Nat. Cell Biol. 2007; 9: 436-444Crossref PubMed Scopus (190) Google Scholar, 16Zhu C. Lau E. Schwarzenbacher R. Bossy-Wetzel E. Jiang W. Spatiotemporal control of spindle midzone formation by PRC1 in human cells.Proc. Natl. Acad. Sci. USA. 2006; 103: 6196-6201Crossref PubMed Scopus (116) Google Scholar]. Dephosphorylation of Ase1 by the phosphatase Cdc14 turns out to be a key event in the formation of a centered spindle midzone [10Khmelinskii A. Lawrence C. Roostalu J. Schiebel E. Cdc14-regulated midzone assembly controls anaphase B.J. Cell Biol. 2007; 177: 981-993Crossref PubMed Scopus (114) Google Scholar]. The finding that many microtubule-associated proteins diffuse laterally along microtubules [17Brouhard G.J. Stear J.H. Noetzel T.L. Al-Bassam J. Kinoshita K. Harrison S.C. Howard J. Hyman A.A. XMAP215 is a processive microtubule polymerase.Cell. 2008; 132: 79-88Abstract Full Text Full Text PDF PubMed Scopus (343) Google Scholar] suggests ways in which midzonal protein interactions arise. How these interactions then contribute to spindle midzone organization has yet to be determined, however. The current work highlights the importance of a well-organized spindle midzone in fail-safe chromosome segregation. Midzone organization requires the concerted regulation of microtubule bundling, microtubule dynamics, microtubule polarity and microtubule sliding. The underlying protein interaction network is complex and will require large-scale analysis in order for it to be fully understood. Novel imaging methods promise to yield a wealth of information on the spatial regulation of microtubule dynamics within organizing spindles. Imaging the dynamics of individual microtubules is relatively simple in small yeast cells, but important progress has also been made in larger cells [18Yang G. Houghtaling B.R. Gaetz J. Liu J.Z. Danuser G. Kapoor T.M. Architectural dynamics of the meiotic spindle revealed by single-fluorophore imaging.Nat. Cell Biol. 2007; 9: 1233-1242Crossref PubMed Scopus (86) Google Scholar]. Analytical and computational models will finally link knowledge of protein biochemistry and microtubule organization in such a way that a thorough understanding of the regulatory mechanisms is obtained [19Mogilner A. Wollman R. Civelekoglu-Scholey G. Scholey J. Modeling mitosis.Trends Cell Biol. 2006; 16: 88-96Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 20Nedelec F. Computer simulations reveal motor properties generating stable antiparallel microtubule interactions.J. Cell Biol. 2002; 158: 1005-1015Crossref PubMed Scopus (152) Google Scholar] and will also suggest ways in which functional protein modules could interact to orchestrate spindle formation." @default.
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• W2029576146 title "Chromosome Segregation: Organizing Overlap at the Midzone" @default.
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