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Spindly Attachments Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press PERSPECTIVE Spindly attachments Filiz Çivril1 and Andrea Musacchio1,2,3 1Department of Experimental Oncology, European Institute of Oncology, I-20139 Milan, Italy; 2Research Unit of the Italian Institute of Technology (IIT) Foundation at the IFOM-IEO Campus, I-20139 Milan, Italy The attachment of chromosomes to spindle microtu- and associated binding partners in the so-called consti- bules during mitosis is a delicate and intricate process on tutive centromere-associated network (CCAN; also which eukaryotic cells critically depend to maintain known as NAC/CAD) (Cheeseman and Desai 2008). The their ploidy. In this issue of Genes & Development, second module provides the core of the microtubule- Gassmann and colleagues (pp. 2385–2399) present an binding interface. Its most prominent component is the analysis of the recently discovered Spindly/SPDL-1 pro- KNL1–Mis12–Ndc80 complex (KMN) network, an array tein that casts new lights onto the attachment process of 10 proteins (Cheeseman and Desai 2008). Besides cre- and the way it relates to the control of cell cycle progres- ating a receptor for the microtubule, the KMN network sion. also serves as a recruitment pad for additional proteins, including molecular motors like dynein, which have been implicated in the early stages of attachment (see The basics below). Although the points of contact between the first Mitotic prometaphase is quite an eventful phase of the and second modules have not been elucidated, the two eukaryotic cell cycle. Its most characteristic trait is the modules contribute a structural core of the kinetochore mitotic spindle’s frantic engagement in the capture of that physically links chromosomes to spindle microtu- replicated chromosomes (the sister chromatids) that bules (Fig. 1A). have been scattered throughout the cell. Microtubules, The additional modules are implicated in the control the main ingredient of the mitotic spindle, form tight of the state of kinetochore–microtubule attachment. attachments with specialized structures on mitotic chro- One module includes the components of the spindle as- mosomes known as kinetochores. The correct configu- sembly checkpoint (SAC), which are all recruited to ki- ration of kinetochore–microtubule attachment is named netochores in mitosis (Musacchio and Salmon 2007). biorientation (Fig. 1A). When bioriented, the chromatids The SAC alleviates the potentially hazardous conse- in a sister chromatid pair in the mother cell are con- quences of attachment being largely (although not nected to opposite spindle poles (Cheeseman and Desai solely) based on the random encounter of a kinetochore 2008; Tanaka and Desai 2008). Biorientation contributes with a microtubule (Cheeseman and Desai 2008). Within to chromosome congression to the metaphase plate. It a single cell, there can be substantial variability in the also ensures that when the cohesion linking the sisters is timing at which the different chromosomes biorient (for removed at the metaphase-to-anaphase transition, the example, see Meraldi et al. 2004). Conversely, the loss of sisters are separated toward opposite spindle poles to sister chromatid cohesion is always highly synchronous, give rise to two daughter cells with identical genetic ma- and it always follows biorientation of the last sister chro- terial (Fig. 1B). matid pair. The synchronization is due to the SAC (for review, see Musacchio and Salmon 2007). As long as there is even a single unattached chromosome in the The kinetochore mitotic cell, the SAC continues to generate a “wait ana- The 60–80 conserved proteins that populate mitotic ki- phase” signal to prevent loss of sister chromatid cohe- netochores from yeast to humans can be schematically sion and mitotic exit. Once all chromosomes are prop- subdivided into distinct functional modules (for review, erly attached, the SAC signal subsides, sister chromatid see Cheeseman and Desai 2008). The first module is im- cohesion is removed, and the sisters are finally separated plicated in the interaction of kinetochores with centro- into daughter cells that are being concomitantly created meric chromatin, and is built around a specialized through the mitotic exit program (Musacchio and nucleosome containing the histone H3 variant CENP-A Salmon 2007). Through yet another module, kinetochores have also acquired the remarkable ability to regulate the stability [Keywords: Centromere; aneuploidy; mitosis; kinetochore; microtubule; of microtubule attachments, and to recognize and cor- spindle; chromosome] rect attachments that fail to result in biorientation. A 3Corresponding author. E-MAIL [email protected]; FAX 39-02-57489851. crucial piece of machinery in the control of attachment Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1719208. stability is the chromosome–passenger complex, whose 2302 GENES & DEVELOPMENT 22:2302–2307 © 2008 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/08; www.genesdev.org Downloaded from genesdev.cshlp.org on September 26, 2021 - Published by Cold Spring Harbor Laboratory Press New insights into kinetochore–microtubule attachment Figure 1. Complexity of the dynamic kinetochore–microtubule interface. (A) The sister kinetochores of a bioriented sister chromatid pair at metaphase are connected to opposite spindle poles through one or more microtubules (the number of microtubules varies in different species). The closeup shows the configuration of end-on attachment with KMN networks bound to microtubules. (B)At anaphase, the sister chromatids have lost cohesion and are transported to opposite spindle poles. (C) Complexity of the kinetochore– microtubule attachment process. Black arrows indicate an action, such as “recruitment” or “microtubule binding.” Dotted black arrows indicate that an uncertainty exists on the actual species performing the action. Green arrows define positive regulation. Red lines with a smaller perpendicular line at one end indicate negative regulation. We did not distinguish whether the negative or positive regulation is exercised on an action or the species that carries out the action. The KMN network mediates several actions, including kinetochore recruitment of the RZZ complex and of the SAC proteins Mps1, Bub1, BubR1, and Bub3, and the formation of stable end-on microtubule attachments. Most and probably all of the actions ascribed to the KMN network are positively regulated by the Aurora B kinase. Aurora B also suppresses improper kinetochore–microtubule attachments. The checkpoint proteins (in blue) posi- tively regulate the process of end-on attachment. In the case of Mps1, this may occur through a positive regulation of Aurora B activity. In the case of Bub1 and BubR1, the target of regulation by these kinases is unknown. After recruitment to prometaphase kinetochores, the RZZ complex suppresses the ability of the KMN network to bind to microtubules. Once at kinetochore, the RZZ complex recruits Spindly, dynein, Mad1, and Mad2. Dynein mediates lateral attachment to microtubules, which in turn favors end-on attachment. The establishment of end-on attachment suppresses the kinetochore accumulation of the RZZ and of the other proteins whose kinetochore localization depends on the RZZ, as it instates the mechanism of “stripping.” See the text for details and references supporting this scheme. most renowned component is the Aurora B kinase tachment (Tanaka and Desai 2008). Early during the at- (Ruchaud et al. 2007). tachment process, kinetochores interact laterally with If a modular subdivision is a useful aid to grasp the microtubules, and in many species this initial attach- basic functions of kinetochores, current analyses have to ment results in rapid poleward movement of the at- address the molecular complexity of kinetochores, in tached chromosome (see below). At later stages, how- particular, the way in which different modules control ever, kinetochores become engaged in so-called end-on each other dynamically. Elements of this regulation are attachments, in which the kinetochores are tethered to continuing to emerge. For instance, it is now clear that the microtubule plus end through a “sliding collar” the main piece of microtubule attachment machinery, whose motility is processively coupled to the polymer- the KMN network, is responsible for the recruitment ization and depolymerization of kinetochore microtu- and release of the SAC components to/from kineto- bules (Tanaka and Desai 2008). The formation of end-on chores, and that the Aurora B kinase phosphorylates attachments is critical for biorientation and for the gen- KMN network components to regulate their binding af- eration of load bearing attachments. It is also necessary finity for microtubules and their ability to recruit the for the decline of the SAC signal prior to anaphase SAC (Fig. 1C; Musacchio and Salmon 2007; Cheeseman (Musacchio and Salmon 2007). and Desai 2008). These examples, which will be ana- Recent work from several laboratories supports the lyzed more thoroughly below, are forcing a shift of para- conclusion that the components of the KMN network digm in the way we think about the dynamic kinetocho- contribute the main interface for microtubule end-on at- re–microtubule interface. tachment (for review, see Cheeseman and Desai 2008). As explained above, the KMN network takes its name The molecular machinery of kinetochore–microtubule from its components, which include KNL-1
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