CELL CYCLE 2016, VOL. 15, NO. 4, 493–497 http://dx.doi.org/10.1080/15384101.2015.1128596


The spindle assembly checkpoint promotes chromosome bi-orientation: A novel Mad1 role in chromosome alignment Takashi Akeray and Yoshinori Watanabe Laboratory of Chromosome Dynamics, Institute of Molecular Cellular Biosciences, University of Tokyo, Tokyo, Japan



Faithful chromosome segregation relies on dynamic interactions between spindle microtubules and chromosomes. Especially, all chromosomes must be aligned at the equator of the spindle to establish biorientation before they start to segregate. The spindle assembly checkpoint (SAC) monitors this process, inhibiting chromosome segregation until all chromosomes achieve bi-orientation. The original concept of ‘checkpoints’ was proposed as an external surveillance system that does not play an active role in the process it monitors. However, accumulating evidence from recent studies suggests that SAC components do play an active role in chromosome bi-orientation. In this review, we highlight a novel Mad1 role in chromosome alignment, which is the first conserved mechanism that links the SAC and kinesin-mediated chromosome gliding.

Received 16 November 2015 Accepted 27 November 2015

Introduction Chromosome segregation is an essential process by which genetic information is passed to daughter cells. This process depends on the microtubule-based machine called the spindle. The spindle interacts with chromosomes mainly through kinetochores, which are formed on the centromeric DNA. Kinetochores of sister chromatids should attach to microtubules emanating from opposite spindle poles to be segregated equally to daughter cells (chromosome bi-orientation).1-3 Chromosome alignment at the spindle equator greatly promotes chromosome bi-orientation by increasing the chance of sister kinetochores being captured by microtubules from opposite poles2,4 (Fig. 1). Thus, a failure to complete chromosome alignment leads to mis-segregation in anaphase. To avoid this, cells are equipped with a system to check whether all chromosomes are fully aligned or not. This surveillance system is called the spindle assembly checkpoint (SAC). The SAC is specifically activated at unattached kinetochores of misaligned chromosomes and produces a diffusible signal, which inhibits Cdc20, an essential co-activator of the anaphase-promoting complex/cyclosome (APC/C).5-10 Thus, this system enables cells to delay the cell cycle until all kinetochores are attached to microtubules. Mad1, Mad2, Mad3/BubR1, Mps1, Bub1 and Bub3 are considered the core components of the SAC. SAC signaling cascade comprising Aurora B, Mps1, Bub1 and Bub3 recruits Mad1 to unattached kinetochores.11 Mad1 then recruits Mad2 and induces its conformational change to assemble the mitotic checkpoint complex (MCC), which inhibits the APC/C. The original concept of the ‘checkpoint’ was proposed as an external surveillance system that does not play an active role in


kinesin; kinetochore; mitosis; spindle assembly checkpoint

the process it monitors.12 However, there are numbers of studies reporting that SAC components actively promote chromosome bi-orientation, implying the necessity of extending the original concept of the SAC. In this review, we highlight the active roles of SAC components in chromosome bi-orientation with an especial focus on a novel role played by Mad1 in chromosome alignment.

Active roles of SAC components in chromosome bi-orientation Chromosomes achieve bi-orientation after several rounds of trial and error microtubule attachment. Erroneous attachments that do not produce tension across sister kinetochores are destabilized by the chromosome passenger complex (CPC), which contains Aurora B kinase13 (Fig. 2). This allows the kinetochores to proceed to the next round of microtubule attachment. One of the core SAC components, Bub1 kinase, phosphorylates histone H2A to recruit shugoshin, an adaptor for the CPC, to the inner-centromere where the CPC acts for error-correction3,14 (Fig. 2). Another core SAC component, BubR1 associates directly with PP2A-B56 phosphatase to counteract the Aurora B kinase activity, thereby stabilizing the kinetochore-microtubule attachment15-17 (Fig. 2). The most downstream factor in SAC signaling, Mad2, also stabilizes kinetochore-microtubule attachment by affecting the centromeric localization of the CPC18 (Fig. 2). Interestingly, this function does not depend on the kinetochore localization of Mad2. A fine-tuned balance between CPC and counteracting phosphatases is known to be crucial for establishing chromosome

CONTACT Yoshinori Watanabe [email protected] Laboratory of Chromosome Dynamics; Institute of Molecular Cellular Biosciences; University of Tokyo; Tokyo;113-0032, Japan. Color versions of one or more of the figures in this article can be found online at www.tandfonline.com/kccy. y Current address: Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA. © 2016 Taylor & Francis Group, LLC



Figure 1. The spindle assembly checkpoint (SAC) ensures the fidelity of chromosome segregation. In early stage of mitosis, misaligned chromosomes activate the SAC to inhibit APC/C. This prevents premature onset of chromosome segregation. Only when all chromosomes achieve chromosome bi-orientation, the SAC will be inactivated to allow cells to start chromosome segregation.

bi-orientation. These findings suggest that SAC components play important roles in actively promoting chromosome biorientation.

compared to mad3D cells.22 All these findings imply that Mad1 has a role in chromosome bi-orientation beyond the SAC at kinetochores.

A novel Mad1 role in chromosome bi-orientation beyond the SAC

Mad1 promotes chromosome alignment by anchoring Cut7/kinesin-5 to the kinetochore in fission yeast

Another core SAC component, Mad1 is also implicated in promoting chromosome bi-orientation. In fly, mad1-null mutant cells show higher rate of lagging chromosomes in anaphase compared to mad2-null mutant cells.19 This indicates Mad1 has a role in chromosome bi-orientation beyond the SAC. Interestingly, this role depends on Mad2-interacting motif of Mad1, although mad2-null mutant cells undergo normal anaphase.19 Molecular mechanisms how Mad1 promotes chromosome bi-orientation remain elusive. Similarly, in fission yeast, mad1D cells show higher sensitivity to spindle drugs compared to mad2D or mad3D cells.20,21 Importantly, other SAC mutant cells that abolish Mad1 kinetochore localization also showed hypersensitivity to spindle drugs. Also in budding yeast, mad1D and other SAC mutant cells that abolish Mad1 kinetochore localization showed hypersensitivity to spindle drugs

Figure 2. The SAC components play an active role in establishing chromosome biorientation. Bub1 targets the CPC to the inner centromere through phospho-histon H2A-bound Shugoshin. BubR1 targets PP2A-B56 phosphatase, which counteracts CPC, to kinetochore. Mad2 has Mad1-independent role to affect centromeric localization of Aurora B.

A recent study revealed that Mad1 promotes chromosome alignment to establish bi-orientation in both fission yeast and human cells.21 By screening for protein-protein interactions, Cut7/kinesin-5 was identified as a novel protein that interacts with fission yeast Mad1. Through this direct association, Mad1 recruits Cut7 to unattached kinetochores of misaligned chromosomes21 (Fig. 3). Time-lapse imaging of mitotic cells has demonstrated that kinetochore-localized Cut7 drives the gliding of misaligned chromosomes toward the spindle equator. Given that kinesin-5 family members including Cut7 are essential to form the bipolar spindle, Cut7 is a dual-function kinesin required for both spindle bipolarity and chromosome bi-orientation (Fig. 3). Kinesin-5 family members form a homotetramer to crosslink and slide antiparallel microtubules to establish the bipolar spindle.23-31 On the other hand, kinetochore kinesins, which promote chromosome alignments such as CENP-E/ kinesin-7,32,33 form a homodimer.34,35 Curiously, when different Cut7 constructs are artificially anchored to kinetochores, only the dimer form could promote chromosome alignment.21 In addition, Mad1 binds to the carboxyl-terminal region of Cut7 required for its tetramerization.21 While the dimerization of endogenous Cut7 is not proven, these results suggest that Mad1 binding might convert Cut7 from a homotetramer to a homodimer to switch the function from antiparallel microtubule sliding to chromosome gliding. Further in vivo and in vitro analyses of the Mad1-Cut7 complex should help to clarify this point in the future.

Human Mad1 promotes chromosome alignment by anchoring CENP-E/kinesin-7 to the kinetochore In human cells, it was unclear whether Mad1 played an additional role in chromosome bi-orientation beyond the SAC.



Figure 3. Mad1 has a conserved role in chromosome alignment. In fission yeast, Mad1 targets both Cut7/kinesin-5 and Mad2 to unattached kinetochores to glide misaligned chromosomes and activate the SAC. In human cells, hMad1 utilizes CENP-E/kinesin-7 instead of Eg5/kinesin-5 for chromosome gliding. Both in fission yeast and in human cells, kinesin-5 motor protein plays an essential role in spindle bipolarity.

Recently, however, time-lapse imaging analysis has revealed that Mad1 is required for chromosome alignment in human cells as well.21 Curiously, in human cells, Mad1 anchors different motor protein, CENP-E/kinesin-7, to promote chromosome alignment, whereas Eg5/kinesin-5 does not localize at kinetochores.21 Thus, although Cut7/kinesin-5 functions in chromosome alignment and bipolar spindle formation in fission yeast, human cells utilize CENP-E/kinesin-7 instead of Eg5/kinesin-5 for chromosome alignment (Fig. 3).

Evolutionary conservation of Mad1-kinesin pathway Budding yeast kinesin-5 motor proteins Cin8 and Kip1 are required for chromosome alignment.36 Given that budding yeast Mad1 is implicated in chromosome bi-orientation beyond the SAC,22 the Mad1-kinesin-5 pathway might be conserved in fungi. However, in higher eukaryotes such as fly, frog and humans, CENP-E/kinesin-7 homologues are known to promote chromosome alignment instead of Eg5/kinesin-5 homologues.37-40 Since both kinesin-5 and kinesin-7 are plus-end directed processive kinesins,41 and since yeasts have no CENPE/kinesin-7 homolog, CENP-E might be a specialized kinesin that evolved to replace the centromeric Eg5/kinesin-5 function in animals. Notably, recent study revealed that the unusually elongated stalk of CENP-E has an essential role in chromosome

alignment, because “Bonsai” CENP-E with a shortened stalk is unable to achieve a stable lateral attachment, a prerequisite for chromosome gliding.42 It is reasonable to speculate that the stalk of the kinetochore kinesin became longer during evolution in higher eukaryotes because their chromosomes assemble much larger kinetochores than those of yeasts.

Kinetochore kinesins at the right place at the right time It has been observed that CENP-E shows SAC component-like localization at the unattached kinetochores of misaligned chromosomes.43 This localization is quite reasonable since misaligned chromosomes have to glide to the spindle equator depending on the motor activity of CENP-E. In frog, one of the core SAC components, BubR1, has been shown to be required for CENP-E localization to the kinetochore.44 The interaction between CENP-E and BubR1 is similarly detected in human cells.45 However, because BubR1 is dispensable for recruiting CENP-E,46 the biological significance of this interaction remains unknown. As discussed above, a recent study revealed that Mad1 is required for CENP-E localization to unaligned chromosomes in human cells. Human Mad1 associates directly with the previously identified kinetochore-binding domain of CENP-E.21,45 Taken altogether, these results resolve the question of how kinetochore kinesins are specifically targeted only to misaligned chromosomes.

Identification of a conserved motif in Mad1 for kinesin binding

Figure 4. Conserved motif in Mad1 for kinesin binding. Domain organization of Mad1, showing that kinesin-binding motif (dark blue) locates in the unstructured amino-terminal region (light blue). Asterisks show the position of kinesin-binding motif in the sequence alignment. The kinesin-binding motif is conserved from yeasts to humans.

The Mad1 protein possesses a long coiled-coil domain that covers almost its entire length. Earlier biochemical analyses have shown that most of the functional domains of Mad1, such as the Bub1-binding site47 and the Mad2-interacting motif,48 locate in the carboxyl-terminal half of the protein (Fig. 4). The function of the amino-terminal half has remained elusive until recently. It has been shown that the amino-terminal half of Mad1 contains a nuclear pore binding site.49,50 Several functions are reported for Mad1 localizing at the nuclear pore: pre-mitotic anaphase inhibitor formation,49 Mad1-Mad2 proteostasis,51 and the regulation of nuclear-cytoplasmic



transport.52 Most recently, the kinesin-binding motif was mapped at the very end of the amino-terminus, which associates directly with Cut7/kinesin-5 in fission yeast and with CENP-E/kinesin-7 in human cells21 (Fig. 4). Because the kinesin-binding motif of Mad1 is conserved between fission yeast and humans, Cut7 and CENP-E might possess an unknown common module for Mad1 binding.

would provide greater insight into the eukaryotic evolution of the SAC, kinetochores and chromosome gliding.

Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed.

References Conclusions and perspectives Here, we highlight recent studies showing that SAC components are directly involved in the regulation of chromosome gliding and kinetochore-microtubule attachment to establish chromosome bi-orientation. Since many chromosomes in early mitosis are misaligned and activate the SAC, the necessity for chromosome gliding and activation of the SAC arises at the same time. Thus, it is reasonable that these 2 events are linked and controlled by a single factor, Mad1. Given that Cut7/kinesin-5 is essential for bipolar spindle formation, these findings provide new insights into the evolutionary relationship among bipolar spindle formation, chromosome alignment and SAC activation.

What is the meaning of Mad1-kinesin complex localization at the spindle pole? A study in fission yeast revealed that while Mad1 recruits Cut7 to kinetochores, Cut7 in turn acts to recruit Mad1 to the spindle pole.21 Also in mammalian cells, the SAC components and CENP-E localize to the spindle pole depending on dynein after the SAC is satisfied.43,53 Thus, the Mad1-kinesin complex localizes at the spindle pole after SAC silencing, although the biological significance of this spindle pole localization remains unknown. Considering the finding that Mad1-kinesin complex functions in chromosome gliding, it is reasonable to think that the Mad1-kinesin complex that appears near the spindle pole facilitates loading of the ‘glider complex’ onto misaligned chromosomes, which often locate near the pole. Future studies to dissect the role of the Mad1-kinesin complex at kinetochores and at the spindle pole will examine this hypothesis.

Did the SAC and chromosome gliding mechanism co-evolve? Upstream factors of Mad1 in SAC signaling, such as Mps1, Bub1 and Bub3, are essential for the kinetochore localization of Mad1.11 Therefore, it is likely that all these core SAC components contribute to the chromosome gliding process through the Mad1-kinesin complex. Indeed, the chromosome bi-orientation defects of mph1D, bub1D and bub3D mutant cells in fission yeast are partly rescued by artificially tethering Cut7 to the kinetochores.21 Thus, the whole SAC signaling cascade at the kinetochore contributes to anchoring kinesin in addition to forming MCC, strengthening the notion that the SAC signaling cascade has co-evolved with a chromosome gliding mechanism. Notably, the ancient eukaryote Trypanosoma brucei, which possesses unconventional kinetochores, does not have the SAC, and the Mad2 homolog does not localize at the kinetochores.54 Studying the chromosome gliding mechanism in this organism

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The spindle assembly checkpoint promotes chromosome bi-orientation: A novel Mad1 role in chromosome alignment.

Faithful chromosome segregation relies on dynamic interactions between spindle microtubules and chromosomes. Especially, all chromosomes must be align...
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