Human DNA is organized into 46 chromosomes, which must be duplicated before a cell divides and are then shared equally between the two new cells. When this process goes awry, the new cells either have too many or too few chromosomes. This situation – known as aneuploidy – frequently occurs in cancer cells, and is thought to cause cells to gain extra copies or lose copies of genes that promote or prevent cancer, respectively.

Cells have several ways to prevent aneuploidy. One of these safeguards, known as the spindle assembly checkpoint (SAC), involves a protein called BubR1, which acts at the stage when the duplicated chromosomes need to be equally divided into each daughter cell. Mouse models show that low levels of the BubR1 protein result in aneuploidy and increased predisposition to cancer. High levels of BubR1, on the other hand, allow the mice to stay healthier for longer and can stop tumors from forming. However, it was not known exactly how high amounts of BubR1 protect against cancer.

To address this question, Weaver et al. set out to determine which parts, or domains, of the BubR1 protein protect against cancer. Mice with high levels of the full-length BubR1 protein were compared with mice that made mutant versions of BubR1 lacking certain domains. These experiments revealed that a small portion of the beginning of the protein was necessary to protect against tumor formation, but removing a large region in the middle of BubR1 still protected mice against lung cancer and aneuploidy. Additional experiments performed on mouse cells grown in the laboratory revealed that whole BubR1 protein and the mutant protein lacking the middle region might prevent aneuploidy in multiple ways. For example, both systems had stronger SAC signaling, which could serve to make segregating the chromosomes more accurate.

In the future, it will be important to find out whether BubR1 acts in the same way in human cells and cancers. Lastly, since it is not possible to over-produce BubR1 in humans, other methods will need to be investigated to use this knowledge to treat cancer.

Chromosomal instability (CIN) describes a condition where cells frequently acquire cytogenetic alterations and do not accurately segregate their chromosomes (Giam and Rancati, 2015). Aneuploidy, defined as a state in which there are alterations to whole chromosome copy number, results from CIN and is a feature of almost all tumors, but whether aneuploidy is a cause or consequence of transformation is the subject of much debate (Ricke and van Deursen, 2013). CIN is thought to allow pre-neoplastic cells to acquire genes that promote tumor progression and lose those which suppress transformation (Baker et al., 2009; Burrell et al., 2013; Hanahan and Weinberg, 2011; Loeb, 2011) and there are multiple lines of evidence which support aneuploidy having a causative role for cancer. For instance, several human aneuploidy syndromes are characterized by increased susceptibility to cancer, including trisomies 8, 18 (Edwards syndrome) and 21 (Down Syndrome) (Ganmore et al., 2009), and mosaic variegated aneuploidy (MVA) (Hanks et al., 2004; Snape et al., 2011). Furthermore, bidirectional deviations in protein levels of various mitotic regulators, including Mad2, Mad1 and Bub1, cause aneuploidy and tumor predisposition in mice (Iwanaga et al., 2007; Jeganathan et al., 2007; Michel et al., 2001; Ricke et al., 2011; Ryan et al., 2012; Sotillo et al., 2007). Additionally, modulations to a spectrum of other proteins that participate in diverse cellular functions, such as the E2 ubiquitin-conjugating enzyme Ubch10 (van Ree et al., 2010), the centromere-linked microtubule protein CENP-E (Weaver et al., 2007), and the nuclear pore complex protein Nup88 (Naylor et al., 2016) result in aneuploidy and accelerated cancer progression. Finally, genome-wide screens of proteins that negatively (STOP) and positively (GO) regulate proliferation are recurrently and selectively lost and gained respectively in either focal regions or whole chromosomes (Davoli et al., 2013; Solimini et al., 2012). This suggests a model where changes in gene copy number are under selection rather than simply accompanying transformation, supporting genomic instability as a driver of cancer (Davoli et al., 2013; Solimini et al., 2012). On the other hand, several other mouse models of CIN have revealed inconsistent results regarding the relationship between aneuploidy and cancer, where some mouse models with elevated levels of aneuploidy do not show increased susceptibility to cancer (Babu et al., 2003; Kalitsis et al., 2005; Ricke et al., 2012). Furthermore, proteotoxic stress from increased gene expression in cells with extra chromosome copies has adverse effects on cell growth and may thus counteract cancer progression (Tang et al., 2011; Williams et al., 2008).

Aneuploidy results when cells fail to segregate chromosomes properly. To promote high-fidelity separation of duplicated chromosomes, cells have the machinery to safeguard against missegregation. One such mechanism is the spindle assembly checkpoint (SAC). This surveillance system prevents activation of the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C) by its co-activator, Cdc20 (Peters, 2006). This ensures chromosomal stability by preventing sister chromatid separation prior to bi-orientation of mitotic chromosomes at the metaphase plate (Musacchio and Salmon, 2007). An additional measure to promote accurate chromosome segregation is allowing sufficient time to form proper and correct erroneous kinetochore-microtubule (MT-KT) attachments prior to anaphase onset (Meraldi et al., 2004). Merotely, a type of improper attachment in which a single kinetochore is attached to microtubules emanating from both spindle poles, is undetected by the SAC and can result in lagging chromosomes (Cimini et al., 2001; Rodriguez-Bravo et al., 2014). Mad1/2, Mps1, and BubR1 specify the minimum time in mitosis, and loss of these proteins reduces the duration of mitosis and increases the rates of missegregation (Maciejowski et al., 2010; Meraldi et al., 2004; Rodriguez-Bravo et al., 2014).

BubR1, along with Mad2 and Bub3, is a component of the mitotic checkpoint complex (MCC), which mediates the SAC (Kulukian et al., 2009; Musacchio and Salmon, 2007; Sudakin et al., 2001). Once each chromosome has properly and stably attached to the mitotic spindle and sufficient inter-kinetochore tension is generated, the MCC dissociates, allowing Cdc20 to activate the APC/C (Musacchio and Salmon, 2007). Co-activation of APC/C by Cdc20 in metaphase results in the polyubiquitination and subsequent proteasomal degradation of cyclin B1 and securin, thereby triggering sister chromatid separation and anaphase onset (Kapanidou et al., 2015; Musacchio and Salmon, 2007). BubR1, encoded by the gene Bub1b in mice or BUB1B in humans, is a modular protein, with several known functional domains that together ensure mitotic fidelity and genome stability. BubR1 localizes to the kinetochore by interacting through its GLEBs-like motif with Bub3 (Elowe et al., 2010; Lampson and Kapoor, 2005). In human cells, kinetochore-localized BubR1 was shown to be important for MT-KT stabilization through an internally located kinetochore attachment and regulatory domain (KARD) (Suijkerbuijk et al., 2012). The KARD allows kinetochore localization of the phosphatase PP2A, which counteracts the MT-KT destabilizing activity of Aurora B kinase, a key mediator of error-correction (Ruchaud et al., 2007; Suijkerbuijk et al., 2012). Additional BubR1 functional domains include a putative kinase/pseudokinase domain that has been reported to reinforce the SAC and stabilize MT-KT attachments (Elowe, 2011; Harris et al., 2005; Suijkerbuijk et al., 2012) and two Cdc20-binding domains, of which the N-terminal domain (BubR1^N) is a critical APC/C^Cdc20 inhibitor essential for cell survival (Malureanu et al., 2009). BubR1^N contains two KEN-boxes, spanning amino acids 19–21 (KEN1) and 298–300 (KEN2) in mice, that in conjunction with a destruction (D)-box (D1) just downstream of KEN2 permits BubR1 to behave as a pseudo-substrate inhibitor of APC/C^Cdc20(Burton and Solomon, 2007; Chao et al., 2012; Han et al., 2013; Izawa and Pines, 2015; Malureanu et al., 2009). Recent work has highlighted that BubR1 is capable of binding both soluble Cdc20 through KEN1 to prevent APC/C-Cdc20 association, and a second Cdc20 that has already bound to and activated the APC/C through a combination of KEN2 and D1 for even more dynamic APC/C^Cdc20 inhibition (Izawa and Pines, 2015).

The second Cdc20-binding domain of BubR1, BubR1^I, is an internally located and functionally distinct region important for Cdc20 kinetochore recruitment, and has been proposed to serve a dual function in SAC activation and silencing (Chao et al., 2012; Di Fiore et al., 2015; Diaz-Martinez et al., 2015; Izawa and Pines, 2015; Lischetti et al., 2014; Tang et al., 2001). Several conserved and somewhat redundant motifs within BubR1^I were recently identified that are thought to promote the BubR1-Cdc20 interaction through complementary mechanisms: the ABBA motif, named for its conserved presence in Acm1, Bub1, BubR1 and Cyclin A (Di Fiore et al., 2015); the Phe box, a phenylalanine-containing region which is encompassed within the ABBA motif (Diaz-Martinez et al., 2015); and a D-box just downstream of the Phe Box (D-box2) (Diaz-Martinez et al., 2015).

Whereas bidirectional changes to protein levels of Mad1, Bub1 and Mad2 cause aneuploidy and tumorigenesis (Ricke and van Deursen, 2013), BubR1 is unique amongst mitotic regulators in that both under- and overexpression results in drastically different phenotypes (Baker et al., 2013; Baker et al., 2004). Complete loss of BubR1 causes early embryonic death (Wang et al., 2004), and while BubR1 hypomorphic (Bub1b^H/H) mice are viable, they develop a variety of premature aging phenotypes (Baker et al., 2004; Hartman et al., 2007; Kyuragi et al., 2015; Matsumoto et al., 2007; North et al., 2014), progressive aneuploidy (Baker et al., 2004), and are predisposed to carcinogen-induced cancers (Baker et al., 2006). Additionally, in humans, mutations in BUB1B have been causally implicated in MVA, a rare clinical syndrome characterized by widespread aneuploidy, growth retardation, shortened lifespan, and cancer predisposition (García-Castillo et al., 2008; Hanks et al., 2004; Matsuura et al., 2006; Wijshake et al., 2012). Conversely, overexpression of BubR1 extends life- and healthspan of mice, decreases the tumor incidence, and provides protection against age-related phenotypes in tissues that are prone to increased aneuploidy rates with age (Baker et al., 2013).

Despite profound anti-tumor and anti-aneuploidization effects of BubR1 overexpression, the molecular mechanism(s) of how it prevents CIN and cancer remains unclear (Baker et al., 2013). Here, we focus on the role of BubR1-Cdc20 binding, and explore how this interaction reinforces the SAC and error-correction machinery by using a series of transgenic mice overexpressing BubR1 mutants with disruptions in Cdc20-binding domains. We show that overexpression of a mutant BubR1 that includes disruptions of the internal Cdc20-binding domain (BubR1^∆I) elicits a tumor-protective mechanism similar to that of full-length (FL)-BubR1 overexpression. Importantly, like in FL-Bub1b, overexpression of this mutant also safeguards against aneuploidization, likely by both strengthening SAC signaling and preventing improper KT-MT attachments. Thus, the internal Cdc20-binding domain is dispensable to mediate these protective effects, while the N-terminal Cdc20-binding domain is necessary, but not sufficient. BubR1^∆I also provides distinct molecular properties unique to that of overexpression alone that also likely promote genetic stability and show no overt detrimental effects on cells or mice. This includes a more robust SAC that is more responsive to weak stimuli, and an increase in the normal length of mitosis. With further refined mutant Bub1b constructs, we demonstrate that a maximal SAC response can be achieved exclusively by the loss of the Phe box and D-box2, and that the mitotic timing may be dependent on previously uncharacterized regions of BubR1. Importantly, this work sheds light on the causal role of CIN in cancer by demonstrating that enhancing genomic stability fortifies the barriers of transformation, and may provide unique insights into the generation of new therapeutic strategies.

BubR1 is different from other mitotic regulators in that supranormal expression improves numerical chromosomal integrity. Although it will be impractical to overexpress BubR1 for therapeutic purposes, increased insight into the molecular mechanisms underlying the positive effects of BubR1 overexpression might create entry points for development of novel anti-cancer treatments based on small molecules that complement current therapies. As a first step, we focused on the roles of BubR1’s Cdc20-binding domains. Here we show that overexpression of the BubR1 N-terminal region is necessary, but not sufficient to prevent Kras-mediated aneuploidy and tumorigenesis, implying that reinforcing pseudo-substrate inhibition of Cdc20-bound APC/C by BubR1 is a requirement but entirely ineffective in isolation. In contrast to the N-terminal Cdc20-binding domain, a region spanning residues 525–700 that includes the elements of the internal Cdc20-binding domain and KARD, is dispensable for the aneuploidy and tumor suppressing effects. Overexpression of BubR1 lacking this region reinforced genomic stability and cancer protection in mice, despite dramatically altering metaphase duration of regularly dividing, unchallenged, MEF cells. We find that key shared characteristics of overexpressed FL-BubR1 and BubR1^ΔI include increased kinetochore localization, increased error correction ability and a more robust SAC, though at differing magnitudes. BubR1^ΔI overexpression was most extreme in altering the SAC in that it appeared to lower the threshold for checkpoint activation and maintenance. By analyzing the mitotic phenotypes of more refined deletion mutants, we determined that the profound length of nocodazole-induced mitotic arrest in this mutant was likely provided by a combined loss of the Phe box and D-box2, which is in alignment to a previous report showing that this region normally serves to shorten mitotic arrest times (Diaz-Martinez et al., 2015). However, whether the increased duration of mitotic arrest is actively participating in attenuation of Kras-mediated tumorigenesis in either FL-Bub1b or Bub1b^∆I Kras^La1 mice is unclear, as oncogenic Kras alone did not negatively impact SAC signaling in MEFs.

Another unique attribute of BubR1^∆I overexpression was its impact on normal mitotic timing. In pursuing this phenotype, we found that while overexpression of BubR1^∆PheD recapitulated the robust nocodazole arrest seen in Bub1b MEFs, it did not reproduce the extension of the metaphase-to-anaphase transition. We further explored this with a mutant BubR1 lacking a combination of the Phe box, D-box2 and KARD (Bub1b^{∆Phe∆KARD}), but also did not see changes to mitotic timing. This suggests that the loss of a region within BubR1 between residues 525 and 700, either alone or in combination with the aforementioned domains, might be responsible for influencing the duration of mitosis. Further expansion of this notion could assign new functions related to timing to previously unmapped regions of BubR1.

Our studies in MEFs which had been infected with oncogenic Kras illuminated that while they had normal mitotic timing and SAC signaling, they had challenges with proper error correction machinery. Taken altogether, these data suggest that specific manipulations of BubR1 and subsequent protection against aneuploidy can occur through distinct complimentary mechanisms that result in tumor protection. In FL-Bub1b and Bub1b^ΔI, parameters that positively influence genomic stability such as a robust SAC and improved error correction correlate with loss of Kras-mediated aneuploidy and tumorigenesis. Therefore, it is tempting to speculate that the strongest mechanism preventing aneuploidization in our Kras system might be a strengthening of the error correction machinery. Given the heterogeneous nature of lung tumors compared to MEFs, however, it is possible that distinct challenges and defects can arise in Kras lung tumors that are not overtly evident in MEFs.

Lung tissues with activated oncogenic Kras proceed through several morphological stages, including regions of mild hyperplasia/dysplasia that have increased aneuploidy relative to normal lung tissue, to small alveolar adenomas and finally culminating into overt carcinoma (Baker et al., 2013; Johnson et al., 2001). We proposed two distinct but non-mutually exclusive mechanisms of tumor protection. In the first mechanism, the impact of a hypersensitive SAC combined with an ability to promote proper attachments and prevent misalignments by FL-BubR1 and BubR1^ΔI simply prevents genetic heterogeneity that facilitates cancer progression. Thus, while hyperplasia is still a feature of the lungs, there is a block to full neoplastic transformation because necessary losses of tumor suppressors and gains of cancer promoting genes are prevented.

The second scenario is that survival of pre-neoplastic cells within the hyperplastic tissue is impacted by BubR1 overexpression, such that unstable cells have an increased propensity to die. The competing-networks model proposes that two independent yet competing cell fates oppose each other during mitotic arrest: death by caspase-mediated apoptosis or mitotic slippage resulting from persistent cyclin B1 degradation due to incomplete SAC inhibition (Brito and Rieder, 2006; Gascoigne and Taylor, 2008; Topham et al., 2015). Cells with prolonged mitotic arrest have a greater chance and more time to accumulate death signals (Gascoigne and Taylor, 2008). Both mutants have an impact on one arm of the competing network branches, as evidenced by their increase in arrest time in mitosis, though BubR1^ΔI appears to have a more significant contribution. This could shift a given cell population towards death rather than survival. However, this hypothesis remains to be rigorously tested in our model especially since oncogenic Kras-infected MEF cells do not show evidence of a weakened mitotic checkpoint. We argue that taking advantage of an extended arrest independent of whether or not the machinery functions normally could still be used to promote cancer cell death, and that BubR1 overexpression would be an entry point to such therapies. Along these lines, microtubules have been targeted in anti-cancer chemotherapy with much success (Dumontet and Jordan, 2010). Furthermore, the use of Wee/Chk1 inhibitors which cause cells to bypass the G2 checkpoint, force reliance on the SAC (Mc Gee, 2015). This could be exploited and we would predict an increased susceptibility to microtubule poisons and cytotoxicity, in particular with a system mimicking BubR1^ΔI or BubR1^ΔPheD overexpression.

Previously we reported a non-significant increase in the mitotic arrest time of MEFs overexpressing FL-BubR1 when challenged with nocodazole relative to wild-type (Baker et al., 2013). Here, we conclude, based on more in depth and sophisticated studies to test this aspect of SAC signaling, that there is a modest but significant increase in SAC potency in these cells (Baker et al., 2013). Furthermore, overexpression of BubR1^∆Phe, BubR1^∆D, and BubR1^∆KARD deletion constructs in wild-type MEFs also provided a slight but significant increase in mitotic arrest time compared to controls, indicating that they were analogous to FL-BubR1 overexpression alone. It is important to note that the data provided by the extensive analysis of Bub1b^∆I and Bub1b^∆KARD MEFs are in disagreement with previous work in human cells, where the KARD was proposed to provide the MT-KT attachment function of BubR1 (Suijkerbuijk et al., 2012). In these studies, introducing exogenous BubR1 with a mutated KARD into systems depleted of endogenous BubR1 have decreased PP2A kinetochore localization, and subsequent chromosome alignment defects (Suijkerbuijk et al., 2012). In Bub1b^ΔI MEFs, however, we do not see increased alignment errors or decreased PP2A kinetochore localization (Table 2, Figure 5—figure supplement 1) and both overexpressed BubR1^∆I and BubR1^∆KARD actually have increased error correction capabilities (Figure 7B, Figure 9C). We emphasize that unlike the studies by Suijkerbuijk and colleagues, our transgene and deletion construct are on the background of a full complement of endogenous BubR1, which may still provide adequate kinetochore docking of PP2A. Furthermore, our data are also in alignment with our previous work in which BubR1^∆I expressed on a BubR1^–/– background does not show overt increases in misalignments (Malureanu et al., 2009). This could represent species-specific differences in the reliance of the KARD for attachment, or on the dependency of BubR1 to recruit PP2A to the kinetochore.

Overexpression of BubR1^ΔN or its complimentary fragment BubR1^N does not recapitulate benefits observed with FL-BubR1 and BubR1^ΔI overexpression. Instead, BubR1^ΔN may be imposing detrimental effects on the cells, as its overexpression results in a slight increase in aneuploidy and a decreased ability to sustain a checkpoint arrest in MEFs, though in vivo aneuploidy rates do not change. Interestingly, however, while the BubR1 N-terminus appears necessary for physiological benefits, it alone did not exert an anti-tumor effect. FL-Bub1b and Bub1b^ΔI MEFs have increased BubR1 expression at kinetochores (Figure 2B), corresponding to phenotypic benefits. BubR1^N cannot localize to kinetochores, in addition to lacking several functional domains such as the putative kinase/pseudokinase domain, the internal Cdc20-binding domain, and KARD. As we have determined from the studies herein that the internal binding domain and KARD are dispensable, kinetochore localization and subsequent action of BubR1 there might be key to beneficial phenotypes, in particular, error attachment (Lampson and Kapoor, 2005). This is in agreement with our previous study in which we found BubR1 that is unable to localize to kinetochores due to disruptions of the Bub3-binding domain cannot fully rescue spindle assembly checkpoint or mediate complete corrective effects on misalignment in cells depleted of endogenous BubR1 (Malureanu et al., 2009). The use of transgenic strains in which BubR1^N is artificially tethered to kinetochores and evaluating the impact on SAC and error correction signaling could shed light on this in future studies (Maldonado and Kapoor, 2011). Other transgenic models could parse out the specific contribution of kinetochore-localized overexpression to tumor prevention with a domain mutant that does not permit BubR1 to localize to the kinetochore, as well as overexpression of a kinase-dead BubR1.

Whether or not aneuploidy causes cancer or is simply a feature is a longstanding question (Giam and Rancati, 2015). Here, we offer a unique perspective by showing the reinforcement of genomic stability through several complimentary mechanisms, with an emphasis on error correction machinery, attenuates tumors in a Kras mouse model of lung cancer. Tumor cells often have compromised DNA repair pathways, and are therefore sensitized to chemotherapies such as topoisomerase inhibitors and alkylating agents that promote cellular damage (Calderón-Montaño et al., 2014). There are few, if any, cancer treatments that revolve around promoting chromosomal stability and reinforcing known checkpoint pathways. Thus, by forcing reliance on the SAC and death in mitosis by damaging or bypassing other cell-cycle checkpoints, a more potent anti-tumor therapy could be designed.

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Author details

1. Robbyn L Weaver

   Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States

   Contribution

   RLW, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

2. Jazeel F Limzerwala

   Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States

   Contribution

   JFL, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

3. Ryan M Naylor

   Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States

   Contribution

   RMN, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

4. Karthik B Jeganathan

   Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, United States

   Contribution

   KBJ, Acquisition of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

5. Darren J Baker

   1. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
   2. Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, United States

   Contribution

   DJB, Acquisition of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

6. Jan M van Deursen

   1. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States
   2. Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, United States

   Contribution

   JMvD, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   vandeursen.jan@mayo.edu

   Competing interests

   The authors declare that no competing interests exist.

   "This ORCID iD identifies the author of this article:" 0000-0002-3042-5267

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