Ricke et al. reveal that mice expressing an inactive version of the mitotic kinase Bub1 aren’t susceptible to cancer, even though they frequently mis-segregate their chromosomes.
Bub1 is an essential protein that has several functions in mitosis, including activation of the mitotic checkpoint, which prevents cells from entering anaphase until every chromosome is correctly attached to the mitotic spindle. Mice expressing reduced or excessive amounts of Bub1 show chromosome segregation defects, aneuploidy, and increased rates of tumor development. The contribution of Bub1’s kinase activity to these processes is unclear, however.
Ricke et al. generated mice expressing a kinase-dead version of Bub1 (Bub1KD) in place of the wild-type protein. Aside from a slight decrease in male fertility, these animals were perfectly healthy, despite showing high levels of chromosome missegregation and aneuploidy. Mitotic checkpoint proteins were still recruited to kinetochores in the absence of Bub1 kinase activity, but the Aurora B kinase, which destabilizes incorrect kinetochore–spindle attachments, failed to accumulate at the centromeres of Bub1KD cells, resulting in the misalignment of mitotic chromosomes. Bub1 promoted Aurora B’s recruitment to centromeres by phosphorylating histone H2A on threonine 121.
Though aneuploidy is thought to drive tumorigenesis, Bub1KD mice were no more prone to tumors than wild-type animals. This suggests that, although Bub1 suppresses tumors by promoting accurate chromosome segregation, its kinase activity is required for some other step in tumor progression. The authors now want to investigate whether the viability of Bub1KD cells is dependent on the closely related protein BubR1.
Text by Ben Short