Model for how tumor develops in K243R/+ mice. BubR1 acetylation plays dual roles: it is required for stable maintenance of the KT–MT interaction and for SAC maintenance. K243R/+ cells exhibit congression failure because 50% of BubR1 is acetylation deficient. Acetylation-deficient BubR1 (K243R) is incapable of recruiting PP2A-B56α to counteract excessive Aurora B kinase activity at the KMN network, and this process is crucial for stable KT–MT interaction. K243R also has reduced CENP-E binding, which may contribute to the problem in chromosome congression (left). Half of the SAC complex contains K243R-BubR1 and fails to maintain SAC activity. K243R associates with other MCC components; however, the protein is readily ubiquitinated by the APC/C, resulting in disassociation of MCC. As initial SAC signal generation is intact, premature disassembly of MCC leads to failure in the maintenance of SAC, effectively weakening SAC activity. The combined effects of chromosome–spindle attachment failure and weakened SAC lead to massive chromosome missegregation and initiate tumorigenesis in K243R/+ mice.