BUB1 and BUBR1: Multifaceted kinases of the cell cycle

Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, CB2 1GA. Cambridge, England.
Trends in Biochemical Sciences (Impact Factor: 13.52). 09/2010; 36(3):141-50. DOI: 10.1016/j.tibs.2010.08.004
Source: PubMed

ABSTRACT The multidomain protein kinases BUB1 and BUBR1 (Mad3 in yeast, worms and plants) are central components of the mitotic checkpoint for spindle assembly (SAC). This evolutionarily conserved and essential self-monitoring system of the eukaryotic cell cycle ensures the high fidelity of chromosome segregation by delaying the onset of anaphase until all chromosomes are properly bi-oriented on the mitotic spindle. Despite their amino acid sequence conservation and similar domain organization, BUB1 and BUBR1 perform different functions in the SAC. Recent structural information provides crucial molecular insights into the regulation and recognition of BUB1 and BUBR1, and a solid foundation to dissect the roles of these proteins in the control of chromosome segregation in normal and oncogenic cells.

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Available from: Victor M Bolanos-Garcia, Aug 22, 2015
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    • "The interaction of SAC kinases Bub1 and BubR1 with the protein Knl1 physically links SAC signaling with the kinetochore (Kiyomitsu et al., 2007, 2011; Bolanos-Garcia et al., 2011). The crystal structure of N-terminal Knl1 with TPR BubR1 defines an extensive hydrophobic interface in which a mechanistic zipper mode of binding has been suggested. "
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    ABSTRACT: The control of chromosome segregation relies on the spindle assembly checkpoint (SAC), a complex regulatory system that ensures the high fidelity of chromosome segregation in higher organisms by delaying the onset of anaphase until each chromosome is properly hi-oriented on the mitotic spindle. Central to this process is the establishment of multiple yet specific protein-protein interactions in a narrow time-space window. Here we discuss the highly dynamic nature of multi-protein complexes that control chromosome segregation in which an intricate network of weak but cooperative interactions modulate signal amplification to ensure a proper SAC response. We also discuss the current structural understanding of the communication between the SAC and the kinetochore; how transient interactions can regulate the assembly and disassembly of the SAC as well as the challenges and opportunities for the definition and the manipulation of the flow of information in SAC signaling.
    Frontiers in Physiology 09/2014; 5:1-11. DOI:10.3389/fphys.2014.00368 · 3.50 Impact Factor
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    • "The multidomain protein kinases BUB1 (budding uninhibited by benzimidazole 1) and the above-described BUBR1 (in yeasts, worms, and plants, termed also Mad3-mitotic-arrest deficient) represent the central part of the control point in the mitotic spindle ready for assembly. This evolutionarily preserved and indispensable system of self-control in the eukaryotic cell cycle warrants a high quality of chromosomal segregation by delaying the manifestation of anaphase in all chromosomes that are incorrectly bioriented to mitotic spindles; it takes part in the inhibition of anaphase-promoting complex/cyclosome (Shichiri et al. 2002; Greene et al. 2008; Lee et al. 2009; Frio et al. 2010; Bolanos-Garcia and Blundell 2011; Nasir et al. 2011). A number of authors have described a high activity of BUBR1, which may be linked to the progression of the epithelial form of ovarian tumors. "
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    ABSTRACT: BUBR1 (budding uninhibited by benzimidazole-related 1) represents the component of a controlling complex in mitosis. Defects in mitotic control complex result in chromosomal instability and, as a result, disturb the mitotic process. This study was aimed at examining the prognostic value linked to the expression of BUBR1 in a group of patients with breast cancer. We analyzed the expression of BUBR1 in 98 stage II breast cancer patients with a median follow-up of 15 years. Immunohistochemical reactions were performed using monoclonal antibodies against BUBR1. We also studied the prognostic value of BUBR1 mRNA expression using the Kaplan-Meier (KM) plotter, which assessed the effect of 22,277 genes on survival in 2422 breast cancer patients. A background database was established using gene expression data and survival information on 2422 patients downloaded from the Gene Expression Omnibus (GEO; Affymetrix HGU133A and HGU133+2 microarrays). The median relapse-free survival was 6.43 years. Univariate and multivariate analyses showed that higher expression of BUBR1 was typical for cases of shorter overall survival, disease-free time, and disease-specific survival. KM plotter analysis showed that elevated BUBR1 mRNA expression had a negative impact on patients’ relapse-free, distant metastases–free, and overall survival. Elevated BUBR1 expression was associated with poor survival in early stage breast cancer patients.
    Journal of Histochemistry and Cytochemistry 02/2013; 61(5). DOI:10.1369/0022155413480148 · 2.40 Impact Factor
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    ABSTRACT: Biochemical studies suggest that caspase activity is required for a functional mitotic checkpoint (MC) and mitotic slippage. To test this directly, we followed nontransformed human telomerase immortalized human retinal pigment epithelia (RPE-1) cells through mitosis after inhibiting or depleting selected caspases. We found that inhibiting caspases individually, in combination, or in toto did not affect the duration or fidelity of mitosis in otherwise untreated cells. When satisfaction of the MC was prevented with 500 nM nocodazole or 2.5 μM dimethylenastron (an Eg5 inhibitor), 92-100% of RPE-1 cells slipped from mitosis in the presence of pan-caspase inhibitors or after simultaneously depleting caspase-3 and -9, and they did so with the same kinetics (~21-22 h) as after treatment with nocodazole or Eg5 inhibitors alone. Surprisingly, inhibiting or depleting caspase-9 alone doubled the number of nocodazole-treated, but not Eg5-inhibited, cells that died in mitosis. In addition, inhibiting or depleting caspase-9 and -3 together accelerated the rate of slippage ~40% (to ~13-15 h). Finally, nocodazole-treated cells that recently slipped through mitosis in the presence or absence of pan-caspase inhibitors contained numerous BubR1 foci in their nuclei. From these data, we conclude that caspase activity is not required for a functional MC or for mitotic slippage.
    Molecular biology of the cell 05/2011; 22(14):2470-9. DOI:10.1091/mbc.E11-03-0228 · 5.98 Impact Factor
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