Figure 1.

Model Showing the Functions of BUB1 and BUBR1 in the Mitotic Spindle Checkpoint during Mitotic Progression

(A) In prometaphase, the nuclear envelope breaks down and microtubules emanating from opposite poles attach to the kinetochores of individual sister chromatids. Core checkpoint components BUB1, BUBR1, BUB3, MAD1, and MAD2 are recruited to unattached kinetochores in SAC-activated cells. Kinetochore localization of BUB1 and BUBR1 is mediated by the mitotic kinetochore protein Blinkin. The latter also establishes physical interaction with the MIS12 and NDC80 complexes. Cytosolic BUBR1, BUB3, MAD2, and CDC20 associate to form mitotic checkpoint complexes, which interact with the anaphase promoter complex/cyclosome (APC/C) to render it inactive.

(B) In metaphase, the bipolar attachment and alignment of all chromosomes at the center of the cell is reached and APC/C-CDC20 inhibition released by silencing of the SAC. This is followed by the onset of anaphase, in which sister chromatids separate and are pulled toward opposite poles of the cell. When the checkpoint is silenced, securing can be ubiquitinated by APC/C and degraded. This results in the release and activation of separase, which leads to the cleavage of mitotic cohesions at centromeres and chromosome arms to cause chromosome separation and mitotic progression from M-phase to interphase.