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 (BubR1(N)) and internal (BubR1(I)) Cdc20-binding domains of BubR1 in preventing aneuploidy and safeguarding against cancer. BubR1(N) 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 BubR1(I) 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.
Highlights
Chromosomal instability (CIN) describes a condition where cells frequently acquire cytogenetic alterations and do not accurately segregate their chromosomes (Giam and Rancati, 2015)
Western blots of mouse embryonic fibroblasts (MEFs) and lung tissue from 5-month old mice revealed that each of the three BubR1 mutants was expressed at levels comparable to that of FL-BubR1
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
Summary
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.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
