The chromosomal passenger complex and the spindle assembly checkpoint: kinetochore-microtubule error correction and beyond

During mitosis, correct bipolar chromosome attachment to the mitotic spindle is an essential prerequisite for the equal segregation of chromosomes. The spindle assembly checkpoint can prevent chromosome segregation as long as not all chromosome pairs have obtained bipolar attachment to the spindle. The chromosomal passenger complex plays a crucial role during chromosome alignment by correcting faulty chromosome-spindle interactions (e.g. attachments that do not generate tension). In the process of doing so, the chromosomal passenger complex generates unattached chromosomes, a specific situation that is known to promote checkpoint activity. However, several studies have implicated an additional, more direct role for the chromosomal passenger complex in enforcing the mitotic arrest imposed by the spindle assembly checkpoint. In this review, we discuss the different roles played by the chromosomal passenger complex in ensuring proper mitotic checkpoint function. Additionally, we discuss the possibility that besides monitoring the presence of unattached kinetochores, the spindle assembly checkpoint may also be capable of responding to chromosome-microtubule interactions that do not generate tension and we propose experimental set-ups to study this

The chromosomal passenger complex: guiding Aurora-B through mitosis

During mitosis, the chromosomal passenger complex (CPC) orchestrates highly different processes, such as chromosome alignment, histone modification, and cytokinesis. Proper and timely localization of this complex is the key to precise control over the enzymatic core of the CPC, the Aurora-B kinase. We discuss the molecular mechanisms by which the CPC members direct the dynamic localization of the complex throughout cell division. Also, we summarize posttranslational modifications that occur on the CPC and discuss their roles in regulating localization and function of this mitotic complex

A dCas9-based system identifies a central role for Ctf19 in kinetochore-derived suppression of meiotic recombination

In meiosis, crossover (CO) formation between homologous chromosomes is essential for faithful segregation. However, misplaced meiotic recombination can have catastrophic consequences on genome stability. Within pericentromeres, COs are associated with meiotic chromosome missegregation. In organisms ranging from yeast to humans, pericentromeric COs are repressed. We previously identified a role for the kinetochore-associated Ctf19 complex (Ctf19c) in pericentromeric CO suppression. Here, we develop a dCas9/CRISPR-based system that allows ectopic targeting of Ctf19c-subunits. Using this approach, we query sufficiency in meiotic CO suppression, and identify Ctf19 as a mediator of kinetochore-associated CO control. The effect of Ctf19 is encoded in its NH2-terminal tail, and depends on residues important for the recruitment of the Scc2-Scc4 cohesin regulator. This work provides insight into kinetochore-derived control of meiotic recombination. We establish an experimental platform to investigate and manipulate meiotic CO control. This platform can easily be adapted in order to investigate other aspects of chromosome biology

The kinetochore prevents centromere-proximal crossover recombination during meiosis

During meiosis, crossover recombination is essential to link homologous chromosomes and drive faithful chromosome segregation. Crossover recombination is non-random across the genome, and centromere-proximal crossovers are associated with an increased risk of aneuploidy, including Trisomy 21 in humans. Here, we identify the conserved Ctf19/CCAN kinetochore sub-complex as a major factor that minimizes potentially deleterious centromere-proximal crossovers in budding yeast. We uncover multi-layered suppression of pericentromeric recombination by the Ctf19 complex, operating across distinct chromosomal distances. The Ctf19 complex prevents meiotic DNA break formation, the initiating event of recombination, proximal to the centromere. The Ctf19 complex independently drives the enrichment of cohesin throughout the broader pericentromere to suppress crossovers, but not DNA breaks. This non-canonical role of the kinetochore in defining a chromosome domain that is refractory to crossovers adds a new layer of functionality by which the kinetochore prevents the incidence of chromosome segregation errors that generate aneuploid gametes. DOI: http://dx.doi.org/10.7554/eLife.10850.00

Checkpoint control in meiotic prophase: Idiosyncratic demands require unique characteristics

Chromosomal transactions such as replication, recombination and segregation are monitored by cell cycle checkpoint cascades. These checkpoints ensure the proper execution of processes that are needed for faithful genome inheritance from one cell to the next, and across generations. In meiotic prophase, a specialized checkpoint monitors defining events of meiosis: programmed DNA break formation, followed by dedicated repair through recombination based on interhomolog (IH) crossovers. This checkpoint shares molecular characteristics with canonical DNA damage checkpoints active during somatic cell cycles. However, idiosyncratic requirements of meiotic prophase have introduced unique features in this signaling cascade. In this review, we discuss the unique features of the meiotic prophase checkpoint. While being related to canonical DNA damage checkpoint cascades, the meiotic prophase checkpoint also shows similarities with the spindle assembly checkpoint (SAC) that guards chromosome segregation. We highlight these emerging similarities in the signaling logic of the checkpoints that govern meiotic prophase and chromosome segregation, and how thinking of these similarities can help us better understand meiotic prophase control. We also discuss work showing that, when aberrantly expressed, components of the meiotic prophase checkpoint might alter DNA repair fidelity and chromosome segregation in cancer cells. Considering checkpoint function in light of demands imposed by the special characteristics of meiotic prophase helps us understand checkpoint integration into the meiotic cell cycle machinery

The chromosomal passenger complex and the spindle assembly checkpoint: kinetochore-microtubule error correction and beyond-1

obtain bipolar spindle attachments, improper attachments (syntelic – depicted here-, and merotelic attachments) need to be corrected to prevent chromosome segregation errors. Aurora B in complex with its fellow passenger proteins is necessary for this correction process. Through the phosphorylation of kinetochore proteins that bind microtubules it modifies the stability or affinity of the kinetochore-microtubule interaction. As a consequence microtubules detach from the kinetochore allowing new rounds of attachments until bipolarity is obtained. However, during this correction process unattached are created capable of inhibiting the APC/C [33]. As such Aurora B's role in checkpoint function can be considered an indirect consequence of its microtubule destabilising activity.<p><b>Copyright information:</b></p><p>Taken from "The chromosomal passenger complex and the spindle assembly checkpoint: kinetochore-microtubule error correction and beyond"</p><p>http://www.celldiv.com/content/3/1/10</p><p>Cell Division 2008;3():10-10.</p><p>Published online 28 May 2008</p><p>PMCID:PMC2430558.</p><p></p

The chromosomal passenger complex and the spindle assembly checkpoint: kinetochore-microtubule error correction and beyond-2

S, the chromosomal passenger complex not only destabilises these attachments but also elicits an additional signal that inhibits the APC/C [35]. This could be via direct phosphorylation of APC/C subunits, or via direct control of the spindle assembly checkpoint. Ways be which the chromosomal passenger complex could exert direct control over the spindle checkpoint are through regulation of BubR1/Bub1 kinetochore levels, modulation of the mitotic checkpoint complex or via an as yet unknown pathway. Regardless the mechanism, this additional signal is thought to amplify the unattached kinetochore-derived signal, resulting in a robust checkpoint response when the number of unattached kinetochores is low.<p><b>Copyright information:</b></p><p>Taken from "The chromosomal passenger complex and the spindle assembly checkpoint: kinetochore-microtubule error correction and beyond"</p><p>http://www.celldiv.com/content/3/1/10</p><p>Cell Division 2008;3():10-10.</p><p>Published online 28 May 2008</p><p>PMCID:PMC2430558.</p><p></p

The chromosomal passenger complex and the spindle assembly checkpoint: kinetochore-microtubule error correction and beyond-0

NP (which results in knock-down of all chromosomal passenger complex components). Transfected cells were released from a 24 h thymidine block into the indicated drugs. Eighteen hours after the release cells were fixed and prepared for FACS analysis. The MPM2 antibody was used to determine the mitotic index. This type of experiment shows that knock-down of a classical checkpoint protein (Mad2) does not allow cells to accumulate in mitosis with any of the drugs, while knock-down of the chromosomal passenger complex affects the response to paclitaxel and monastrol more dramatically than the response to nocodazole.<p><b>Copyright information:</b></p><p>Taken from "The chromosomal passenger complex and the spindle assembly checkpoint: kinetochore-microtubule error correction and beyond"</p><p>http://www.celldiv.com/content/3/1/10</p><p>Cell Division 2008;3():10-10.</p><p>Published online 28 May 2008</p><p>PMCID:PMC2430558.</p><p></p

The chromosomal passenger complex and the spindle assembly checkpoint: kinetochore-microtubule error correction and beyond-3

Ever, even when all kinetochores are unattached the spindle assembly checkpoint is not capable of inhibiting all APC/C's which might explain why these cells do eventually exit from mitosis (mitotic slippage) [58]. If Aurora B is inactivated in these cells, less APC/C's will be inhibited. Still this is sufficient to allow a mitotic delay, but this delay is significantly shorter than when Aurora B is active [14, 15]. (B) Treatment with the microtubule stabilising agent paclitaxel induces a mitotic arrest with a few unattached kinetochores [35] most likely inhibiting less APC/C's than when all kinetochores are unattached. Yet, this number of inhibited APC/C's is sufficient to sustain a robust checkpoint-dependent arrest. Since the unattached kinetochores are generated under the influence of the chromosomal passenger complex/Aurora B [35], inhibition of Aurora B will now silence both the unattached kinetochore-derived checkpoint signal and the additional amplification signal, resulting in an override of the spindle assembly checkpoint. (C) Expression of a chromosomal passenger complex that lacks the coiled-coil domain of INCENP does not affect the microtubule destabilising activity of Aurora B. In the presence of paclitaxel unattached kinetochores are therefore generated but this does not result in a checkpoint-dependent arrest [35]. We propose that due to the low number of unattached kinetochores that are now inhibiting the APC/C, the spindle checkpoint becomes more dependent on this additional chromosomal passenger complex-generated amplification signal to inhibit a sufficient number of APC/C's that allow a robust mitotic arrest.<p><b>Copyright information:</b></p><p>Taken from "The chromosomal passenger complex and the spindle assembly checkpoint: kinetochore-microtubule error correction and beyond"</p><p>http://www.celldiv.com/content/3/1/10</p><p>Cell Division 2008;3():10-10.</p><p>Published online 28 May 2008</p><p>PMCID:PMC2430558.</p><p></p