BubR1 alterations that reinforce mitotic surveillance act against aneuploidy and cancer

Abstract

BubR1 is a key component of the spindle assembly checkpoint (SAC). Mutations that reduce BubR1 abundance cause aneuploidization and tumorigenesis in humans and mice, whereas BubR1 overexpression protects against these. However, how supranormal BubR1 expression exerts these beneficial physiological impacts is poorly understood. Here, we used Bub1b mutant transgenic mice to explore the role of the amino-terminal (BubR1N) and internal (BubR1I) Cdc20-binding domains of BubR1 in preventing aneuploidy and safeguarding against cancer. BubR1N was necessary, but not sufficient to protect against aneuploidy and cancer. In contrast, BubR1 lacking the internal Cdc20-binding domain provided protection against both, which coincided with improved microtubule-kinetochore attachment error correction and SAC activity. Maximal SAC reinforcement occurred when both the Phe- and D-box of BubR1I were disrupted. Thus, while under- or overexpression of most mitotic regulators impairs chromosome segregation fidelity, certain manipulations of BubR1 can positively impact this process and therefore be therapeutically exploited.DOI: http://dx.doi.org/10.7554/eLife.16620.001

BubR1 allelic effects drive phenotypic heterogeneity in mosaic-variegated aneuploidy progeria syndrome

“…BUBR1 overexpression was also shown to counteract age-related aneuploidization in various tissues, raising the possibility that inaccurate chromosome segregation may be a driver of tissue deterioration with aging. BUBR1 overexpression appears to reinforce both the spindle assembly checkpoint (SAC) and the mitotic error correction machinery, which may underlie the observed reductions in aneuploidization rates (15).…”

“…A laser-scanning microscope (LSM 880; Carl Zeiss) with an inverted microscope (Axiovert 100M; Carl Zeiss) was used for imaging. The monastrol washout assay was performed as previously described (15). Briefly, 100 μM monastrol (Enzo Life Sciences, catalog BML-GR322) was added to passage-5 MEFs for 60 minutes, followed by the addition of 10 μM MG132 (Sigma-Aldrich, catalog C2211) plus monastrol for an additional 60 minutes.…”

A fine balancing act: A delicate kinase-phosphatase equilibrium that protects against chromosomal instability and cancer

“…In this situation, the high kinetochore BUB1 levels are unaffected, but now BUBR1 is also enhanced and kinetochore substrate phosphorylation is reduced; presumably due to the extra PP2A-B56 that is corecruited by BUBR1, although this was never directly tested. It should be noted, however, that BUBR1 is also able to protect against aneuploidy in different tumour models, and it has been proposed to have pleotropic effects that are independent on PP2A-B56, but maybe related to its ability to engage the SAC (Baker et al, 2013;Weaver et al, 2016).…”

Recent insights into the cellular and molecular determinants of aging

“…Disruption of DNA repair mechanisms or the spindle assembly checkpoint (SAC), which ensures chromosome transmission fidelity, results in accelerated aging (Chen et al, 2011;Gregg et al, 2012;Krishnan et al, 2011;Murga et al, 2009). Accordingly, enhancing SAC activity through overexpression of BubR1, a key component of the checkpoint, prevented aneuploidy in aged mice and extended the lifespan of the animal (Baker et al, 2013;Weaver et al, 2016).…”