title: 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 (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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States.
authors.forename: Robbyn L
authors.initials: RL
authors.lastname: Weaver
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States.
authors.forename: Jazeel F
authors.initials: JF
authors.lastname: Limzerwala
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Naylor
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, United States.
authors.forename: Karthik B
authors.initials: KB
authors.lastname: Jeganathan
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States.|Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, United States.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Baker
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, United States.|Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, United States.
authors.forename: Jan M
authors.identifier: 0000-0002-3042-5267
authors.initials: JM
authors.lastname: van Deursen
mesh_terms: D000782:Aneuploidy; D000818:Animals; D063646:Carcinogenesis; D006801:Humans; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: C584277:BUB1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: BubR1; aneuploidy; cancer; cancer biology; chromosomes; genes; mouse